INTRODUCTION
Oral ulcers is a very common disorder of the oral mucosa. Several predisposing factors have been suggested and oral ulcers can be a feature of various systemic disorders including inflammatory bowel disease. The nature, site, duration and frequency of oral ulcers are determined by the underlying systemic condition. In addition, usually histopathological examination warrants a definitive diagnosis in the majority of conditions described in this paper. Clearly, it is not possible to discuss all oral conditions giving rise to oral mucosal ulcers; hence, the present article will focus on ulcerative disorders either of general clinical significance, or relevant to gastroenterology.
ORAL ULCERS TRAUMATIC AETIOLOGY
Most traumatic ulcers of the mucosa are due to physical trauma. In addition, ulcers may arise with local application of aspirin,1 cocaine or smoking crack cocaine (e.g. on the palate).2 Snorting cocaine may rarely cause necrosis, possibly associated with ischaemia, at the floor of nose and eventual ulcers of the hard palate and oronasal fistula formation.3 Local radiotherapy and some cytotoxic chemotherapy regimes can cause oral mucositis. This manifests as multiple areas of painful mucosal erythema, ulcers and sloughing.4 The precise aetiology of the mucositisremains unclear, although most likely reflects a loss of basal cell proliferation5 rather than a reaction to changes in the local oral microflora (e.g. rises in Gram-negative bacteria, particularly Enterobacteriaceae). 6 This mucositis, akin to that of the bowel, is difficult to manage specifically. Benzydamine hydrochloride mouthrinse or spray may provide symptomatic relief, but often effective analgesia requires opioids. The clinical feature of oral mucositis does not significantly improve with topical chlorhexidine gluconate, although this is commonly used in clinical practice. Novel regimes for the treatment of mucositis include granulocyte- macrophage colony-stimulating factor (GM-CSF) and protegrins, although these are presently in the stages of clinical trial.7, 8
.VIRAL DISEASES: HERPES SIMPLEX INFECTION
A wide range of infections can give rise to oral ulcers. Primary herpes simplex type 1 (HSV-1) remains the most common viral precipitant of ulcers. Affected individuals may have widespread, small, superficial ulcers of the oralmucosa . The gingiva are often swollen and ulcerated, giving rise to features akin to acute necrotizing ulcerative gingivitis (ANUG) (see below). While previously regarded as a disease of childhood, often primary HSV-1 infection arises in the second or third decade of life.9 Severe and/or recurrent HSV-1 infection sometimes presenting atypically may be suggestive of underlying immunodeficiency, in particular lymphoproliferative disease or HIV disease.10 Therapy typically comprises symptomatic relief, although systemic aciclovir and other anti-virals should be considered when disease is severe, recurrent or atypical.13 Aciclovir resistance may arise in immunosuppressed patients receiving repeated therapy, hence the need for famciclovir, valciclovir or foscarnet.11
Herpes simplex virus 2
Although uncommon, HSV-2 can give rise to oral ulcers akin to that of mild primary HSV-1 infection. This oralulcers arises as a consequence of orogenital transmission of the causative virus.
Epstein–Barr virus
Ulcers caused by Epstein–Barr virus (EBV) is rare, but may be a feature of infectious mononucleosis. The ulcers comprises a few small superficial ulcers of the oral mucosa. EBV is more typically associated with the ulcers of some non-Hodgkin’s lymphomas12 or white patches termed oral hairy leukoplakia (OHL) that may arise in immunodeficiency (e.g. HIV disease, corticosteroid or other systemic immunosuppressant therapy, etc.). Of relevance, OHL has been observed in patients with inflammatory bowel disease receiving immunosuppressive regimes.13
Cytomegalovirus
Cytomegalovirus (CMV) may give rise to large, chronic ulcers of the oral mucosa or gingiva.14 These CMVrelated ulcers occur exclusively in significant immunodeficiency, notably severe HIV disease. The diagnosis of such ulcers is difficult and is often only confirmed by resolution of ulcers with ganciclovir therapy.15
Human herpesvirus 8 (Kaposi’s sarcoma herpes virus)
Human herpesvirus 8 (HHV-8) is the cause of Kaposi’s sarcoma (KS), a lesion commonly arising within the mouth of patients with severe HIV disease or a feature of profound iatrogenic immunosuppression (e.g. in patients with inflammatory bowel disease). Oral KS typically affects the palate or gingiva and manifests as red, blue or purple macules, papules, nodules or ulcers.16 Confusingly, oral KS may occasionally be non-pigmented, and hence may mimic SCC.17
Human immunodeficiency virus
The oral consequences of HIV disease are reviewed in detail elsewhere.18,19 Infection with HIV gives rise to a wide spectrum of oral ulcerative lesions. The majority of these are detailed in other sections of the review. A minority of patients with severe HIV disease can develop deep, necrotic ulcers of unknown aetiology . These ulcers are painful, cause profound dysphagia and/or dysarthria and can arise on any oral mucosal surface, although the buccal and pharyngeal mucosae are the more commonly affected sites. The precise aetiology of these HIV-related ulcers is unknown.20 HHV-8 DNA has been detected within these, although whether the virus is causative or merely a passenger remains unclear.21 Of note, the ulcers typically resolve with systemic thalidomide (e.g. 200 mg daily) perhaps reflecting an antitumour necrosis factor (TNF)-a effect in keeping with a viral aetiology.22 Small number of patients with HIV disease may have ulcers similar to that of recurrent aphthous stomatitis (RAS), although whether the frequency of RAS in HIV is truly increased remains unclear.23
BACTERIAL INFECTION
Acute necrotizing ulcerative gingivitis
Acute necrotizing ulcerative gingivitis (Vincent’s disease, trench mouth, acute ulcerative gingivitis) is a nonspecific ulcerative disorder almost always localized to the gingivae.24 Associated contributing factors include poorly controlled diabetes mellitus, tobacco smoking, immunodeficiency (notably severe HIV disease) and possibly psychological stress. Acute necrotizing ulcerative gingivitis manifests as painful ulcers of the gingival margins, particularly the interdental areas. The ulcers may be localized or generalized and when severe will give rise to cervical lymphadenopathy and very rarely pyrexia and malaise. There is often oral malodour. Long-standing or recurrentdisease may lead to destruction and loss of interdental papillae. An ANUG-like disease termed cancrum oris (noma) can arise in profoundly malnourished children and adults. Unlike the ANUG in immunocompetent individuals, the ulcers of cancrum oris spreads to the adjacent soft tissues leading to necrosis of the lips and/or cheeks. Cancrum oris has most commonly been reported in children in Central Africa, the malnourishment arising from poverty because of political and economical unrest.25 An ANUG-like disorder which spreads to the underlying bone and adjacent soft tissues – termed necrotizing stomatitis – has been reported in a small number of patients with severe HIV disease. Occasionally, this disorder may be the first, and/or only clinical manifestation of HIV disease.26 The ulcers of the ANUG typically resolves with the removal of deposits of plaque and calculus and the topical application of chlorhexidine gluconate mouthrinse (0.2%) or gel (1%). Systemic antimicrobials (e.g. metronidazole or phenoxymethyl penicillin) may be required when the gingival is profound and/or there is systemic upset. Cancrum oris additionally requires tissue debridement and correction of the underlying malnourishment, however, the prognosis of affected children is often poor.27 Posthealing fibrosis and scarring is a significant complication of cancrum oris.
Treponema pallidum
The frequency of oral ulcers because of infective syphilis is likely to increase as a consequence of the rising number of subjects affecting with Treponema pallidum.28 Oral ulcers can arise in primary, secondary or tertiary disease. In primary disease, a chancre can develop on the oral mucosa as a consequence of direct contact with an infective lesion. The ulcers of primary infection typically arises on the upper (in females) or lower lip (in males) and manifests as a superficial to deep isolated ulcer sometimes with a rolled edge. Occasionally, there can be isolated ulcers of the gingiva.29 The oral chancre typically resolves with antimicrobial therapy.30 Secondary syphilis can give rise to multiple areas of superficial papules and ulcers, some of the latter being serpiginous and thus termed snail-track ulcers. Tertiary disease may produce ulcers as a consequence of gumma formation, the ulcers manifesting as isolated areas of chronic ulceration sometimes with the destruction of the underlying soft and/or hard tissues (e.g. palate or tongue).
IDIOPATHIC ULCERS
Recurrent aphthous stomatitis
Recurrent aphthous stomatitis is the most common non-infectious and non-traumatic oral mucosal ulcerative disorder. It is characterized clinically by recurrent bouts of oral mucosal ulcers in an otherwise well subject. The ulcers arises every 4–12 weeks and may be classified as minor, major and herpetiform . The ulcers are superficial, rounded and have a yellow coloured slough with surrounding erythema. The ulcers of major RAS may cause scarring on healing, and it has been suggested that the ulcers of herpetiform RAS may coalesce to produce large areas of ulcers that heal with scarring. Rarely major aphthous stomatitis may cause tissue destruction (e.g. of the soft palate). Undoubtedly RAS has an immunologically mediated pathogenesis but the precise cause of RAS remains unclear.31 Suggested aetiologies, include idiopathic haematinic deficiency, cessation of tobacco smoking and psychological stress, but there is little scientific evidence in support of any of these. While superficial ulcers similar to RAS may arise in gluten-sensitive enteropathy,32 the vast majority of patients with RAS have no clinical, gastroenterological or serological features of this small bowel disorder. To date nocommon viral or bacterial infection of the mouth has There is no consistent association between Helicobacter pylori infection and RAS.33 The treatment of RAS remains unsatisfactory. Therapy is directed towards reducing the duration and/or frequency of ulcers.34 The mainstay of therapy is topical corticosteroids, however, few of these have been found to be significantly effective in appropriate clinical studies. Chlorhexidine gluconate mouthrinse may be of some benefit (and has been evaluated in detail), but it really has limited clinical value in the management of RAS. Benzydamine hydrochloride spray or mouthrinseprovides some symptomatic relief but does not hasten ulcer healing. Although effective, systemic therapy with prednisolone is rarely warranted, while the role of immunosuppressants is unclear. Thalidomide is highly effective but in view of the adverse side-effects of teratogenicity and neurotoxicity its routine application for such a recurrent and minor disorder is contraindicated.
ORAL ULCERS RELATED TO SYSTEMIC DISEASE
Gastrointestinal disease
Gluten-sensitive enteropathy. Superficial oral mucosal ulcers similar to RAS may be a feature of 1–5% patients with undiagnosed, untreated gluten-sensitive enteropathy. 35 The ulceration is presumably due to the associated haematinic deficiencies.
Dermatitis herpetiformis and related disorders
Oral lesions in dermatitis herpetiformis have been rarely described. These may comprise oral mucosal vesicles, blood-filled blisters, irregular ulcers and desquamative gingitivitis. Linear IgA disease may likewise give rise to blood-filled vesicles or bullae, irregular ulcers and desquamative gingivitis.36
Crohn’s disease and related disorders
Oral ulcers arises in approximately 9% of patients with undiagnosed Crohn’s disease and can be the first and/or only clinical features of this disorder.37 Two types of oral ulcers can arise in orofacial granulomatosis (OFG) and Crohn’s disease – chronic deep linear ulcers, usually of the buccal vestibules, which often have a rolled edge because of mucosal tags, and superficial oral mucosal ulcers presumably because of haematinic deficiency. The diagnosis of such ulcers requires establishing the presence of non-caseating granulomas and the exclusion of other granulomatous disease such as sarcoidosis .
Ulcerative colitis
Ulcerative colitis can give rise to either aphthous ulcers or multiple pustules termed pyostomatitis vegetans. The ulcers of the latter arise on the upper and lower anterior vestibules, the soft palate and posterior hard palate. Pyostomatitis vegetans tends to arise in patients with undiagnosed or active ulcerative colitis. Although most frequently associated with ulcerative colitis, pyostomatitis vegetans may occasionally arise in Crohn’s disease.38 Pyoderma gangrenosum, manifesting as a solitary, necrotic mucosal ulcer has rarely been reported in the mouth.
DERMATOLOGICAL DISEASE
Lichen planus
Lichen planus is by far the most common dermatological disorder to give rise to oral ulcers. Lichen planus is an immunologically mediated disorder histopathologically characterized by an intense dermal infiltrate of T-lymphocytes. The precise trigger for this immunological reaction is unclear. There is no evidence that the clinical features of idiopathic oral lichen planus are any different to those of drug-associated disease.39 Drugs that may commonly give rise to lichen planus-like disease include sulphonyureas, non-steroidal anti-inflammatory drugs, b-blockers, antimalarials, penicillamine and gold. Associations between hepatitis C virus and oral lichen planus probably reflect the epidemiology of hepatitis C virus infection and/or use of interferon-a.40 are having painful symptoms and/or there are signs of erosion, ulcers or blister formation. Typical treatment comprises topical corticosteroids,41 although severe disease may warrant local (e.g. topical tacrolimus) and systemic immunosuppressant therapy..
MALIGNANCY
The most common tumour of the mouth, and typically manifests as a solitary ulcer of the dorsum of tongue or floor of mouth. The ulceration is locally destructive and when affecting the tongue may give rise to lingual and/ or hypoglossal nerve damage with or without dysarthria or dysphagia. Gingival SCC may give rise to tooth mobility and very rarely a pathological fracture of the mandible. Oral SCC remains one of the more common cancers worldwide, particularly in developing countries such as India.
Non-Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma may manifest as a solitary area of necrotic ulcers typically affecting the gingiva, palate and fauces. This tumour may arise de novo but often is associated with iatrogenic immunosuppression in HIV disease. A detailed review of non-Hodgkin’s lymphoma of the mouth can be found elsewhere.42 NK/ T-cell lymphoma tends to affect the upper anterior gingival and palate; this is a T-cell lymphoma in contrast to most non-Hodgkin’s lymphoma of the mouth.
CONCLUSION
The present article has presented an overview of the common clinical presentations of oral ulceration. Gastrointestinal disease, particularly undiagnosed glutensensitive nteropathy, Crohn’s disease and ulcerative colitis, can give rise to ulcers of the mouth. However, these and other gut diseases can give rise to a range of other oral features , hence, it is important to ask patients who present with gastrointestinal disease about their symptoms and to examine the mouth.
REFERENCES
1 Dellinger TM, Livingston HM. Aspirin burn of the oral cavity. Ann Pharmacother 1998; 32: 1107.
2 Parry J, Porter S, Scully C, Flint S, Parry MG. Mucosal lesions due to oral cocaine use. Br Dent J 1996; 180: 462–4.
3 Lancaster J, Belloso A, Wilson CA, McCormick M. Rare case of naso-oral fistula with extensive osteocartilaginous necrosis
secondary to cocaine abuse: review of otorhinolaryngological presentations in cocaine addicts. J Laryngol Otol 2000; 114:
630–3.
4 Scully C, Epstein J, Sonis S. Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy: Part 2. diagnosis and management of mucositis. Head Neck 2004; 26: 77–84.
5 Potten CS, Booth D, Cragg NJ, et al. Cell kinetic studies in the murine ventral tongue epithelium: mucositis induced by
radiation and its protection by pretreatment with keratinocyte growth factor (KGF). Cell Prolif 2002; 35 (Suppl. 1): 32–47.
6 Stokman MA, Spijkervet FK, Burlage FR, et al. Oral mucositis and selective elimination of oral flora in head and neck cancer
patients receiving radiotherapy: a double-blind randomized clinical trial. Br J Cancer 2003; 88: 1012–6.
7 Mantovani G, Massa E, Astara G, et al. Phase II clinical trial of local use of GM-CSF for prevention and treatment of chemotherapy- and concomitant chemoradiotherapyinduced severe oral mucositis in advanced head and neck cancer patients: an evaluation of effectiveness, safety and costs. Oncol Rep 2003; 10: 197–206.
8 Chen J, Falla TJ, Liu H, et al. Development of protegrins for the treatment and prevention of oral mucositis: structure-activity relationships of synthetic protegrin analogues. Biopolymers 2000; 55: 88–98.
9. Lafferty WE. The changing epidemiology of HSV-1 and HSV-2 and implications for serological testing. Herpes 2002; 9: 51–5.
10. Piluso S, Ficarra G, Lucatorto FM, et al. Cause of oral ulcers in HIV-infected patients: a study of 19 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 82: 166–72.
11. Kleymann G. Novel agents and strategies to treat herpes simplex virus infections. ExpertOpin Investig Drugs 2003; 12: 165–83.
12. Villarreal EC. Current and potential therapies for the treatment of herpes-virus infections. Prog Drug Res 2003; 60: 263–307
13. Szczepanski T, De Vaan GA, Beishuizen A, et al. Acute lymphoblastic leukemia followed by a clonally-unrelated EBV-positive non-Hodgkin lymphoma and a clonally-related myelomonocytic leukemia cutis. Pediatr Blood Cancer 2004; 42: 343–9.
14. Fluckiger R, Laifer G, Itin P, Meyer B, Lang C. Oral hairyleukoplakia in a patient with ulcerative colitisGastroenterology 1994; 106: 506–8.
15. Kanas RJ, Jensen JL, Abrams AM, Wuerker RB. Oral mucosal cytomegalovirus as a manifestation of the acquired immune deficiency syndrome. Oral Surg Oral Med Oral Pathol 1987; 64: 183–9.
16. Flaitz CM, Nichols CM, Hicks MJ. Herpesviridae-associated persistent mucocutaneous ulcers in acquired immunodeficiency syndrome. A clinicopathologic study. Oral SurgOralMedOral Pathol Oral RadiolEndod1996;81:433–41.
17. Lager I, Altini M, Coleman H, Ali H. Oral Kaposi’s sarcoma: a clinicopathologic study from South Africa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 96: 701–10.
18. Reichart PA, Schiodt M. Non-pigmented oral Kaposi’s sarcoma (AIDS). Report of two cases. Int J Oral Maxillofac Surg 1989; 18: 197–9.
19. Scully C, Laskaris G, Pindborg J, Porter SR, Reichart P. Oral manifestations of HIV infection and their management: II. Less common lesions. Oral Surg Oral Med Oral Pathol 1991; 71: 167 71.
20. Scully C, Laskaris G, Pindborg J, Porter SR, Reichart P. Oral manifestations of HIV infection and their management: I. More common lesions. Oral Surg Oral Med Oral Pathol 1991; 71: 158–66.
21. MacPhail LA, Greenspan JS. Oral ulceration in HIV infection: investigation and pathogenesis. Oral Dis 1997; 3 (Suppl. 1): S190–3.
22. Di Alberti L, Porter SR, Speight PM, et al. Detection of human herpesvirus-8 DNA in oral ulcer tissues of HIV-infected individuals. Oral Dis 1997; 3 (Suppl. 1): S133–4.
23. Ramirez-Amador VA, Esquivel-Pedraza L, Ponce-de-Leon S, et al. Thalidomide as therapy for human immunodeficiency virus-related oral ulcers: a double-blind placebo-controlled clinical trial. Clin Infect Dis 1999; 28: 892–4.
24. Ficarra G. Oral ulcers in HIV-infected patients: an update on epidemiology and diagnosis. Oral Dis 1997; 3 (Suppl. 1): S183–9.
25. Novak MJ. Necrotizing ulcerative periodontitis. Ann Periodontol 1999; 4: 74–8.
26. Enwonwu CO, Falkler WA Jr, Idigbe EO, et al. Pathogenesis of cancrum oris (noma): confounding interactions of malnutrition with infection. Am J Trop Med Hyg 1999; 60: 223–32.
27. Jones AC, Gulley ML, Freedman PD. Necrotizing ulcerative stomatitis in human immunodeficiency virusseropositive individuals: a review of the histopathologic, immunohistochemical, and virologic characteristics of 18 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 89: 323–32.
28. Adekeye EO, Ord RA. Cancrum oris: principles of management and reconstructive surgery. J Maxillofac Surg 1983; 11: 160– 70.
29. Alam F, Argiriadou AS, Hodgson TA, Kumar N, Porter SR. Primary syphilis remains a cause of oral ulceration. Br Dent J 2000; 189: 352–4.
30. Steiner M, Alexander WN. Primary syphilis of the gingiva. Report of two cases. Oral Surg Oral Med Oral Pathol 1966; 21: 530–5.
31. Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician 2003; 68: 283–90.
32. Iype EM, Ramdas K, Pandey M, et al. Primary tuberculosis of the tongue: report of three cases. Br J Oral Maxillofac Surg 2001; 39: 402–3.
33. Myoken Y, Sugata T, Kyo TI, Fujihara M. Pathological features of invasive oral aspergillosis in patients with hematologic malignancies. J Oral Maxillofac Surg 1996; 54: 263–70.
34 Loh FC, Yeo JF, Tan WC, Kumarasinghe G. Histoplasmosis presenting as hyperplastic gingival lesion. J Oral Pathol Med 1989; 18: 533–6.
35. Scully C, de Almeida OP. Orofacial manifestations of the systemic mycoses. J Oral Pathol Med 1992; 21: 289–94.
36. Moraru RA, Grossman ME. Palatal necrosis in an AIDS patient: a case of mucormycosis. Cutis 2000; 66: 15–8.
37. Porter SR, Scully C, Pedersen A. Recurrent aphthous stomatitis. Crit Rev Oral Biol Med 1998; 9: 306–21.
38 .Srinivasan U, Weir DG, Feighery C, O’Farrelly C. Emergence of classic enteropathy after longstanding gluten sensitive oral
ulceration. BMJ 1998; 316: 206–7.
39. Porter SR, Barker GR, Scully C, Macfarlane G, Bain L. Serum IgG antibodies to Helicobacter pylori in patients with recurrent aphthous stomatitis and other oral disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 83: 325–8.
40. Porter S, Scully C. Aphthous ulcers: recurrent. Clin Evid 2002; 8: 1397–403.
41. Nowak M, Dziechciarz P, Dwilewicz-Trojaczek J. The frequency of coeliac disease occurrence in patients with recurrent aphthous stomatitis (RAS) – preliminary report. Wiad Lek 2002; 55: 542–6.
42. O’Regan E, Bane A, Flint S, Timon C, Toner M. Linear IgA disease presenting as desquamative gingivitis: a pattern poorly recognized in medicine. Arch Otolaryngol Head Neck Surg 2004; 130: 469–72.
