oral ulceration and its relevance to systemic disorder

8/20/2019 Oral Ulceration and Its Relevance to Systemic Disorder

1/12

Review article: oral ulcers and its relevance to systemic disorders

S . R . P O R T E R * & J . C . L E A O

*Oral Medicine, Division of Maxillofacial Diagnostic, Medical and Surgical Sciences, Eastman Dental Institute for Oral HealthCare Sciences, UCL, University of London, London, UK; Departamento de Clinica e Odontologia Preventiva, Disciplina de

Estomatologia, Universidade Federal de Pernambuco, Brazil

Accepted for publication 9 November 2004

S U M M A R Y

Oral ulceration is a common problem, and is sometimes

a marker of gastroenterological disease. Patients with

signs or symptoms of oral ulcers are sometimes referredto gastroenterology clinics, however, in most instances

the ulcers does not reflect gastrointestinal disease.

Indeed, a spectrum of disorders other than those of

the gut can give rise to oral mucosal ulcers ranging

from minor local trauma to significant local disease

such as malignancy or systemic illness. This present

article reviews aspects of the aetiology, diagnosis andmanagement of common ulcerative disorders of the oral

mucosa.

I N T R O D U C T I O N

Oral ulcers is a very common disorder of the oral

mucosa. Several predisposing factors have been sugges-

ted and oral ulcers can be a feature of various systemic

disorders including inflammatory bowel disease. Thenature, site, duration and frequency of oral ulcers are

determined by the underlying systemic condition. In

addition, usually histopathological examination war-

rants 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.

O R A L U L C E R S T R A U M A T I C A E T I O L O G Y

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 forma-

tion.

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 mucositis

remains 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 Enterobacteria-

ceae).6 This mucositis, akin to that of the bowel, is

difficult to manage specifically. Benzydamine hydro-

chloride 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 granulo-

cyte-macrophage colony-stimulating factor (GM-CSF)

and protegrins, although these are presently in the early

stages of clinical trial.7, 8

Correspondence to: Prof. S. R. Porter, Oral Medicine, Division of Max-

illofacial Diagnostic, Medical and Surgical Sciences, Eastman Dental Insti-

tute for Oral Health Care Sciences, UCL, University of London, 256 Gray’s

Inn Road, London WC1X 8LD, UK.

E-mail: [email protected]

Aliment Pharmacol Ther 2005; 21: 295–306. doi: 10.1111/j.1365-2036.2005.02333.x

2005 Blackwell Publishing Ltd 295


2/12

Necrotizing sialometaplasia

Necrotizing sialometaplasia is an uncommon disorder

that typically gives rise to large areas of deep ulcers of

one side of the hard and/or soft palate.9 Necrotizing

sialometaplasia typically has a traumatic basis and can

be a feature of the bulimia nervosa.10 It is suggested

that the local trauma causes ischaemia with resultanttissue necrosis. The clinical features may mimic those of

squamous cell carcinoma (SCC), and histopathologically

the profound epithelial hyperplasia, together with

salivary gland squamous metaplasia, can be confound

with neoplasia.

V I R A L D I S E A S E S : H E R P E S S I M P L E X I N F E C T I O N

Herpes simplex virus 1

As detailed in Table 1, 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, super-

ficial ulcers of the oral mucosa (Figure 1). 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.11 Severe and/or recurrent

HSV-1 infection sometimes presenting atypically may be

suggestive of underlying immunodeficiency, in particular

lymphoproliferative disease or HIV disease.12

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 immuno-

suppressed patients receiving repeated therapy, hence

the need for famciclovir, valciclovir or foscarnet.14

Interestingly, foscarnet itself may give rise to oral

ulcers,15 and while aciclovir may be effective and useful

in the treatment of erythema multiforme, it can itself

give rise to this mucosal disorder.

About 5% of patients who have primary HSV-1

infection will develop recurrent episodes of herpeslabialis (cold sores). This comprises episodes of paraes-

thesia, erythema, vesiculation, pustulization and ulcers

at the mucocutaneous junctions of the lips and/or nose.

Precipitants of herpes labialis include concurrent illness,

UV light and pregnancy. Effective therapy comprises 5%

aciclovir16 or 1% penciclovir.17 Herpes labialis may

itself be a precipitant of erythema multiforme.18

Herpes simplex virus 2

Although uncommon, HSV-2 can give rise to oral ulcers

akin to that of mild primary HSV-1 infection. This oral

ulcers arises as a consequence of orogenital transmis-

sion 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

Table 1. Infectious causes of oral mucosal ulcers

Viral Herpes group

Human herpes simplex 1

Human herpes simplex 2

Epstein–Barr virus

Varicella zoster virus

Cytomegalovirus

Human herpesvirus 8

(Kaposi’s sarcoma herpesvirus)

Coxsackie viruses (e.g. herpangina,

hand foot and mouth disease)

Human immunodeficiency viruses

Bacterial Treponema pallidum (syphilis)

Acute necrotizing ulcerative gingivitisMycobacterium tuberculosis

Other mycobacterioses

Fungal Candida albicans (uncommon)

Aspergillosis

Paracoccidiodomycosis

Histoplasmosis

Mucormycosis

Protozoal Leishmaniasis

Figure 1. Oral ulcers on the ventral surface of tongue in primary

herpes simplex infection.

296 S . R . P O R TE R & J. C. LE A O

2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 295–306


3/12

ulcers comprises a few small superficial ulcers of the oral

mucosa. EBV is more typically associated with the ulcers

of some non-Hodgkin’s lymphomas19 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 withinflammatory bowel disease receiving immunosuppres-

sive regimes.20

Cytomegalovirus

Cytomegalovirus (CMV) may give rise to large, chronic

ulcers of the oral mucosa or gingiva.21 These CMV-

related ulcers occur exclusively in significant immuno-

deficiency, notably severe HIV disease. The diagnosis of

such ulcers is difficult and is often only confirmed by

resolution of ulcers with ganciclovir therapy.22

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.23 Confusingly, oral KS may occasionally be

non-pigmented, and hence may mimic SCC.

24

Kaposi’s sarcoma of the anterior gingiva may be

unsightly, and rarely gingival lesions will cause destruc-

tion of the underlying periodontal tissues leading to loss

of teeth and sequestration of bone.

Oral KS in HIV disease may reduce or resolve with

highly active antiretroviral therapy (HAART), although

some oral lesions have been reported to resolve

(probably transiently) with local radiotherapy, local

injection of cytotoxics or sclerosants.25–27

Human immunodeficiency virusThe oral consequences of HIV disease are reviewed in

detail elsewhere.28, 29 Infection with HIV gives rise to a

wide spectrum of oral ulcerative lesions (Table 1). 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

(Figure 2). These ulcers are painful, cause profound

dysphagia and/or dysarthria and can arise on any oral

mucosal surface, although the buccal and pharyngealmucosae are the more commonly affected sites. The

precise aetiology of these HIV-related ulcers is

unknown.30 HHV-8 DNA has been detected within

these, although whether the virus is causative or merely

a passenger remains unclear.31 Of note, the ulcers

typically resolve with systemic thalidomide (e.g.

200 mg daily) perhaps reflecting an antitumour necro-

sis factor (TNF)-a effect in keeping with a viral

aetiology.32 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.33

B A C T E R I A L I N F E C T I O N

Acute necrotizing ulcerative gingivitis

Acute necrotizing ulcerative gingivitis (Vincent’s dis-

ease, trench mouth, acute ulcerative gingivitis) is a non-

specific ulcerative disorder almost always localized to

the gingivae.34 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 (Figure 3). 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 recurrent

Figure 2. Deep, necrotic ulcer in HIV infection.

R E V I E W : O R A L U L C E R S A N D S Y S T E MI C DI S O R D E RS 297



4/12

disease may lead to destruction and loss of interdental

papillae.

An ANUG-like disease termed cancrum oris (noma) canarise 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.35

An ANUG-like disorder which spreads to the underly-

ing bone and adjacent soft tissues – termed necrotizing

stomatitis – has been reported in a small number of

patients with severe HIV disease. Occasionally, thisdisorder may be the first, and/or only clinical manifes-

tation of HIV disease.36

The ulcers of the ANUG typically resolves with the

removal of deposits of plaque and calculus and the

topical application of chlorhexidine gluconate mouth-

rinse (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.37 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.38

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) (Figure 4) and manifests as a superficial to deepisolated ulcer sometimes with a rolled edge. Occasion-

ally, there can be isolated ulcers of the gingiva.39 The

oral chancre typically resolves with antimicrobial

therapy.40 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 des-

truction of the underlying soft and/or hard tissues

(e.g. palate or tongue).

Mycobacterial infection

Primary oral infection of Mycobacterium tuberculosis is

rare;41 more commonly, tuberculosis infection of the

oral mucosa arises secondary to pulmonary disease.

Tuberculosis typically presents as solitary, necrotic

ulcers of the tongue. Infection by atypical mycobacteria

(e.g. Mycobacterium avium complex) is rare but may

affect the oral mucosa or gingiva, usually in HIV-

infected individuals.42

Figure 3. Inverted papillae in acute necrotizing ulcerative gingi-

vitis.

Figure 4. Solitary ulcer (chancre) on the lower lip of a patient

diagnosed with primary syphilis.

298 S . R . P O R TE R & J. C. LE A O



5/12

F U N G A L I N F E C T I O N S

While Candida species, usually Candida albicans, is the

most common fungal infection of the mouth, this rarely

gives rise to oral ulcers. Although chronic mucocuta-

neous candidosis (CMC) may occasionally give rise to

ulcers of the dorsum of tongue. Systemic mycoses may

cause oral ulcers, typically in immunosuppressed hosts.In HIV disease, Aspergillus fumigatum may give rise to

long-standing ulcers of the gingiva43 or oral mucosa as

may Histoplasma capsulatum.44 South America paracoc-

cidiodomycosis (South American Blastomycosis) may

give rise to large areas of ulcers reminiscent of oral SCC,

this infection arising in both immunocompetent and

immunosuppressed individuals.45, 46 The other infective

causes of oral ulcers are outlined in Table 2.

I D I O P A T H I C U L C E R S

Recurrent aphthous stomatitis

Recurrent aphthous stomatitis is the most common

non-infectious and non-traumatic oral mucosal ulcera-

tive 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 (Table 3).

The ulcers are superficial, rounded and have a yellow

coloured slough with surrounding erythema. The ulcers

of major RAS (Figure 5) may cause scarring on healing,

and it has been suggested that the ulcers of herpetiformRAS (Figure 6) 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.47 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-sensitiveenteropathy,48 the vast majority of patients with RAS

have no clinical, gastroenterological or serological

features of this small bowel disorder. To date no

common viral or bacterial infection of the mouth has

been implicated in the aetiology of RAS.47 There is no

consistent association between Helicobacter pylori infec-

tion and RAS.49

The treatment of RAS remains unsatisfactory. Therapy

is directed towards reducing the duration and/or

frequency of ulcers.50 The mainstay of therapy is topical

corticosteroids, however, few of these have been found

Table 2. Systemic disease likely to give rise to oral ulcers

Haematological Anaemias

Lymphoproliferative disease

Leukaemias (almost all)

Non-Hodgkin’s lymphoma

Hodgkin’s lymphoma (rare)

Myeloproliferative disease

(usually multiple myeloma)

Myelodysplasias

Neutropenia (any cause)

Gastroenterological Gluten-sensitive enteropathy

Crohn’s disease and related disorders

Dermatitis herpetiformis

Ulcerative colitis

Dermatological Lichen planus

Pemphigus – usually vulgaris,

rarely vegetans, folacous

or paraneoplastic

Pemphigoid – usually mucous membrane,

occasionally bullous

Linear IgA diseaseEpidermylosis bullosa

Others (many)

Immunological Wegener’s granulomatosis

Sarcoidosis

Immunodeficiency (usually defects of

neutrophil number or function)

Malignancy Oral squamous cell carcinoma


Kaposi’s sarcoma

Salivary gland malignancy

(e.g. mucoepidermoid tumour,

adenoid cystic carcinoma)

Metastatic deposits (uncommon)

Drug induced Lichenoid drug reactions (e.g. b-blockers,antimalarials, NSAIDs, interferon)

Erythema multiforme (e.g. barbiturates,

carbamazepine, sulphonamides)

Pemphigus (e.g. penicillamine,

ACE inhibitors, rifampicin)

Lupus (e.g. minocycline, statins, terbinafine)

Pemphigoid (e.g. clonidine, psoralens)

Drug-induced neutropenia/anaemia

(e.g. azathioprine, carbamazepine)

Drug-induced mucositis

(e.g. cyclophosphamide, methotrexate)

Others (e.g. nicorandil)

ACE, angiotensin-converting enzyme; NSAID, non-steroidal anti-

inflammatory drugs; IgA, immunoglobulin A.




6/12

to be significantly effective in appropriate clinical

studies. Chlorhexidine gluconate mouthrinse may be

of some benefit (and has been evaluated in detail),51 but

it really has limited clinical value in the management of

RAS. Benzydamine hydrochloride spray or mouthrinse

provides 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.52–54 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 contraindi-cated.55

Ulcers similar to RAS is one of the cardinal features of

Behcet’s disease. The ulcers has been rarely described in

detail but seem to have the same clinical features as

RAS (Figures 7 and 8). A detailed discussion of Behcet’s

disease can be found elsewhere.56 Other disorders that

can give rise to RAS-like ulcers include a variant of

Behcet’s disease termed MAGIC syndrome, Sweet’s

syndrome and HIV disease.57 A rare disorder in

childhood characterized by pyrexia, pharyngitis,

Table 3. Classification and characteristics of recurrent aphthous

stomatitis

Type

Average

duration

of ulcers

Number

of ulcers Sites

Percentage of

affected

individuals

Minor 1 cm 1–2 Any 10

Herpetiform 1–2 mm 10–100 Any 10*

* Probably an overestimate.

Figure 5. Major recurrent aphthous stomatitis in the oropharix.

Figure 6. Small ulcers in herpetiform recurrent aphthous sto-

matitis.

Figure 7. Oral ulcers in Behcet’s disease.

Figure 8. Pathergy in Behcet’s disease.

300 S . R . P O R TE R & J. C. LE A O



7/12

cervical lymphadenopathy and aphthous-like ulcers

sometimes termed PFAPA (periodic fever, aphthae,

pharyngitis and adenitis) has been described.58

O R A L U L C E R S R E L A T E D T O S Y S T E M I C D I S E A S E

Gastrointestinal diseaseGluten-sensitive enteropathy. Superficial oral mucosal

ulcers similar to RAS may be a feature of 1–5% patients

with undiagnosed, untreated gluten-sensitive enteropa-

thy.59 The ulceration is presumably due to the associ-

ated 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 desquamativegingitivitis. Linear IgA disease may likewise give rise to

blood-filled vesicles or bullae, irregular ulcers and

desquamative gingivitis.60

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.61 Two

types of oral ulcers can arise in orofacial granuloma-

tosis (OFG) and Crohn’s disease (Figures 9 and 10) –

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 thepresence of non-caseating granulomas and the exclu-

sion of other granulomatous disease such as sarcoi-

dosis (Figure 11).

The precise relationship between OFG and gastroin-

testinal Crohn’s disease remains unclear as there are

few studies examining the gastrointestinal tract of

children and adults with OFG. Certainly, there are

reports of OFG being an initial presentation of Crohn’s

disease.62, 63 Likewise, OFG-like disease may be a

feature of patients with concurrent gastrointestinal

Crohn’s disease.64, 65 The human leucocyte antigen

(HLA) haplotype of patients with OFG differs from that

of Crohn’s disease.66 The exact association between

OFG and gastrointestinal Crohn’s disease is thus not

known.

Figure 9. Linear ulcers in orofacial granulomatosis. Figure 11. Gingival enlargement in sarcoidosis.

Figure 10. Irregular superficial ulcers on ventral surface of

tongue in Crohn’s disease.




8/12

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

(Figure 12). 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.67 Pyoderma gangrenosum, manifest-

ing as a solitary, necrotic mucosal ulcer has rarely been

reported in the mouth.68

Others

As discussed above necrotizing sialometaplasia may

arise secondary to palatal trauma in bulimia nervosa.

Gastro-oesophageal reflux does not cause oral ulcera-tion, although it has been associated with erosion of the

palatal aspects of the upper teeth.69

D E R M A T O L O G I C A L D I S E A S E

A spectrum of cutaneous disorders can give rise to oral

ulcers (Table 2).

Lichen planus

Lichen planus is by far the most common dermato-

logical disorder to give rise to oral ulcers. The clinical

features of oral lichen planus are reviewed in Table 4.

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 evi-

dence that the clinical features of idiopathic oral lichen

planus are any different to those of drug-associated

disease.71

Likewise, although histopathological differences

between idiopathic lichen planus and drug-related

disease have been described there is profound inconsis-

tency between the proposed pathological hallmarks of Figure 12. Pyostomatitis vegetans in a patient with ulcerative

colitis.

Table 4. Oral ulcers and other oral manifestations of gastroin-

testinal disease

Gastrointestinal disorder Oral manifestations

Bulimia nervosa Necrotizing sialometaplasia

Superficial oral ulcers

Dental erosion

Bilateral parotid enlargementPost-cricoid webbing Chronic mucocutaneous

candidosis

Gastro-oesophageal

reflux disease

Dental erosion

Gluten-sensitive enteropathy Superficial ulcers

Enamel hypoplasia in children

Dermatitis herpetiformis

(and linear IgA dermatosis)

Vesicles, bullae

Desquamative gingivitis

Enamel hypoplasia (in children)

Peutz-Jegher’s syndrome Perilabial pigmented macules

Cystic fibrosis Enamel hypoplasia

Tetracycline staining of teeth

Superficial oral ulcers

Congenital hepatic disease

and biliary atresia

Pigmentation of the gingivae

Hepatitis C virus infection Xerostomia

Salivary gland disease

Lichen planus (possibly)

Primary biliary cirrhosis Telangiectasia

Xerostomia

Crohn’s disease* Labial (and facial) enlargement

Fissuring of the tongue

Linear ulcers of the buccal

and labial vestibules

Superficial oral ulcersGingival enlargement

Facial nerve palsy

Ulcerative colitis Pyostomatitis vegetans

Pyoderma gangrenosum

Colonic malignancy Superficial oral ulcers

Acanthosis nigricans

* Sometimes disease localized to the mouth is termed orofacial gra-

nulomatosis.

302 S . R . P O R TE R & J. C. LE A O



9/12

these two disorders.72 Drugs that may commonly give

rise to lichen planus-like disease include sulphony-

ureas, non-steroidal anti-inflammatory drugs, b-block-

ers, 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.

73

A lichen planus-like disorder can arise in chronic graft-versus-host

disease.

Lichen planus only warrants treatment in patients

who are having painful symptoms and/or there are

signs of erosion, ulcers or blister formation. Typical

treatment comprises topical corticosteroids,74 although

severe disease may warrant local (e.g. topical tacrol-

imus) and systemic immunosuppressant therapy75, 76

– the use of the latter does not have a strong evidence

base.

Of note, it has been suggested that oral lichen planus

may be potentially malignant. The evidence for this isgenerally based upon retrospective studies of large

numbers of affected patients. It is suggested that

approximately 1–3% of patients with long-standing

lichen planus may develop oral SCC.77 Often, however,

the descriptions have not detailed whether the tumour

has arisen within existing lichen planus and no detailed

prospective control studies of the development of oral

SCC in long-standing lichen planus has ever been

undertaken.

Other dermatological disorders likely to give rise to oral

mucosal ulcers are summarized in Table 2.

H A E M A T O L O G I C A L D I S E A S E

The haematological disorders likely to give rise to oral

ulcers are summarized in Table 2. In general, ulcers

arises as a consequence of haematinic deficiency,

neutropenia and associated opportunistic viral infec-

tion.

M A L I G N A N C Y

The common malignancies of the mouth that may

manifest as oral ulcers are summarized in Table 2. SCC

is 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 dysarth-

ria 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.78–80 Of note, however, there is a rising frequency

of oral SCC in the middle age adult in the developed

world. High tobacco (in any form) and alcoholconsumption are the principal aetiological factors of

oral SCC. Other suggestive aetiologies include human

papilloma virus, malnourishment (in particular defici-

encies of vitamins A and C) and perhaps poor oral

hygiene.


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 immunosuppressionin HIV disease. A detailed review of non-Hodgkin’s

lymphoma of the mouth can be found elsewhere.81 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.82

Drug therapy

A wide range of drugs can give rise to ulcers of the

oral mucosa (Figure 13).

83

The mechanisms by whichdrugs cause oral ulcers include drug-induced neutro-

penia and anaemia (e.g. cytotoxics), lichenoid disease

Figure 13. Drug-induced (nicorandil) oral ulcers on lateral border

of tongue.




10/12

(e.g. sulphanylureas, b-blockers, gold, penicillamine),

pemphigus (e.g. angiotensin-converting enzyme inhib-

itors), lupus disease and IgA dermatoses. Table 5

summarizes the adverse oral side-effects of common

drug therapies of gastrointestinal disease.

C O N C L U S I O N

The present article has presented an overview of the

common clinical presentations of oral ulceration. Gas-

trointestinal disease, particularly undiagnosed gluten-

sensitive enteropathy, 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 (Table 2), hence, it is important to

ask patients who present with gastrointestinal disease

about their symptoms and to examine the mouth

carefully when assessing patients with possible disease

of the gastrointestinal tract.

A C K N O W L E D G E M E N T

JCL is partially funded by a grant from CNPq (Ministry

of Science and Technology), Brazil.

R E F E R E N C E S

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 randomised

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 chemoradiotherapy-

induced 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. Biopolymers2000; 55: 88–98.

9 Koscielny S, Raabe G. Necrotizing sialometaplasia – a specific

differential diagnosis of an ulcer of the hard palate.

Laryngorhinootologie 2003; 82: 568–72.

10 Schoning H, Emshoff R, Kreczy A. Necrotizing sialometaplasia

in two patients with bulimia and chronic vomiting. Int J Oral

Maxillofac Surg 1998; 27: 463–5.

11 Lafferty WE. The changing epidemiology of HSV-1 and HSV-2

and implications for serological testing. Herpes 2002; 9:

51–5.

12 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.

13 Kleymann G. Novel agents and strategies to treat herpes

simplex virus infections. Expert Opin Investig Drugs 2003; 12:

165–83.

14 Villarreal EC. Current and potential therapies for the

treatment of herpes-virus infections. Prog Drug Res 2003;

60: 263–307.

15 Gilquin J, Weiss L, Kazatchkine MD. Genital and oral erosions

induced by foscarnet. Lancet 1990; 335: 287.

16 Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaul-

ding T. Acyclovir cream for treatment of herpes simplex

labialis: results of two randomized, double-blind, vehicle-

controlled, multicenter clinical trials. Antimicrob Agents

Chemother 2002; 46: 2238–43.

17 Sarisky RT, Bacon T, Boon R, et al. Penciclovir susceptibilitiesof herpes simplex virus isolates from patients using penciclovir

cream for treatment of recurrent herpes labialis. Antimicrob

Agents Chemother 2002; 46: 2848–53.

18 Kokuba H, Imafuku S, Huang S, Aurelian L, Burnett JW.

Erythema multiforme lesions are associated with expression of

a herpes simplex virus (HSV) gene and qualitative alterations

in the HSV-specific T-cell response. Br J Dermatol 1998; 138:

952–64.

Table 5. Oral manifestations associated with the therapy of

gastrointestinal disease

Oral manifestation Drugs

Pseudomembranous candidosis Corticosteroids,

immunosuppressants

Chronic erythematous candidosis Corticosteroids,

immunosuppressantsOral hairy leukoplakia Corticosteroids,

immunosuppressants

Xerostomia Omeprazole (rare)

Lingual pigmentation (blue) Dapsone

Gingival enlargement Ciclosporin

304 S . R . P O R TE R & J. C. LE A O



11/12

19 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.

20 Fluckiger R, Laifer G, Itin P, Meyer B, Lang C. Oral hairy

leukoplakia in a patient with ulcerative colitis.

Gastroenterology 1994; 106: 506–8.

21 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.

22 Flaitz CM, Nichols CM, Hicks MJ. Herpesviridae-associated

persistent mucocutaneous ulcers in acquired

immunodeficiency syndrome. A clinicopathologic study. Oral

SurgOralMedOralPatholOralRadiolEndod1996;81:433–41.

23 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.

24 Reichart PA, Schiodt M. Non-pigmented oral Kaposi’s

sarcoma (AIDS). Report of two cases. Int J Oral Maxillofac

Surg 1989; 18: 197–9.25 Diz DP, Ocampo HA, Miralles AC, Vazquez GE, Martinez VC.

Regression of AIDS-related Kaposi’s sarcoma following

ritonavir therapy. Oral Oncol 1998; 34: 236–8.

26 Le Bourgeois JP, Frikha H, Piedbois P, Le Pechoux C, Martin L,

Haddad E. Radiotherapy in the management of epidemic

Kaposi’s sarcoma of the oral cavity, the eyelid and the

genitals. Radiother Oncol 1994; 30: 263–6.

27 Ramirez-Amador V, Esquivel-Pedraza L, Lozada-Nur F, et al.

Intralesional vinblastine vs. 3% sodium tetradecyl sulfate for

the treatment of oral Kaposi’s sarcoma. A double blind,

randomized clinical trial. Oral Oncol 2002; 38: 460–7.

28 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.

29 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.

30 MacPhail LA, Greenspan JS. Oral ulceration in HIV infection:

investigation and pathogenesis. Oral Dis 1997; 3 (Suppl. 1):

S190–3.

31 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.

32 Ramirez-Amador VA, Esquivel-Pedraza L, Ponce-de-Leon S,

et al. Thalidomide as therapy for human immunodeficiencyvirus-related oral ulcers: a double-blind placebo-controlled

clinical trial. Clin Infect Dis 1999; 28: 892–4.

33 Ficarra G. Oral ulcers in HIV-infected patients: an update on

epidemiology and diagnosis. Oral Dis 1997; 3 (Suppl. 1):

S183–9.

34 Novak MJ. Necrotizing ulcerative periodontitis. Ann

Periodontol 1999; 4: 74–8.

35 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.

36 Jones AC, Gulley ML, Freedman PD. Necrotizing

ulcerative stomatitis in human immunodeficiency virus-

seropositive 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.

37 Adekeye EO, Ord RA. Cancrum oris: principles of management

and reconstructive surgery. J Maxillofac Surg 1983; 11: 160–

70.

38 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.

39 Steiner M, Alexander WN. Primary syphilis of the gingiva.

Report of two cases. Oral Surg Oral Med Oral Pathol 1966; 21:

530–5.

40 Brown DL, Frank JE. Diagnosis and management of syphilis.

Am Fam Physician 2003; 68: 283–90.

41 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.

42 Ilyas SE, Chen FF, Hodgson TA, et al. Labial tuberculosis: a

unique cause of lip swelling complicating HIV infection. HIV

Med 2002; 3: 283–6.

43 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.

44 Loh FC, Yeo JF, Tan WC, Kumarasinghe G. Histoplasmosis

presenting as hyperplastic gingival lesion. J Oral Pathol Med

1989; 18: 533–6.

45 Scully C, de Almeida OP. Orofacial manifestations of the

systemic mycoses. J Oral Pathol Med 1992; 21: 289–94.

46 Moraru RA, Grossman ME. Palatal necrosis in an AIDS

patient: a case of mucormycosis. Cutis 2000; 66: 15–8.

47 Porter SR, Scully C, Pedersen A. Recurrent aphthous

stomatitis. Crit Rev Oral Biol Med 1998; 9: 306–21.

48 Srinivasan U, Weir DG, Feighery C, O’Farrelly C. Emergence of

classic enteropathy after longstanding gluten sensitive oral

ulceration. BMJ 1998; 316: 206–7.

49 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.

50 Porter S, Scully C. Aphthous ulcers: recurrent. Clin Evid 2002;8: 1397–403.

51 Hunter L, Addy M. Chlorhexidine gluconate mouthwash in

the management of minor aphthous ulceration. A double-

blind, placebo-controlled cross-over trial. Br Dent J 1987; 162:

106–10.

52 Barrons RW. Treatment strategies for recurrent oral aphthous

ulcers. Am J Health Syst Pharm 2001; 58: 41–50.




12/12

53 MacPhail L. Topical and systemic therapy for recurrent

aphthous stomatitis. Semin Cutan Med Surg 1997; 16:

301–7.

54 Eisen D, Lynch DP. Selecting topical and systemic agents for

recurrent aphthous stomatitis. Cutis 2001; 68: 201–6.

55 Shetty K. Thalidomide for recurrent aphthous ulcerations.

HIV Clin 2003; 15: 4–6.

56 Arayssi T, Hamdan A. New insights into the pathogenesis and

therapy of Behcet’s disease. Curr Opin Pharmacol 2004; 4:

183–8.

57 Femiano F, Gombos F, Scully C. Sweet’s syndrome: recurrent

oral ulceration, pyrexia, thrombophlebitis, and cutaneous

lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod

2003; 95: 324–7.

58 Feder HM Jr. Periodic fever, aphthous stomatitis, pharyngitis,

adenitis: a clinical review of a new syndrome. Curr Opin

Pediatr 2000; 12: 253–6.

59 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.

60 O’Regan E, Bane A, Flint S, Timon C, Toner M. Linear IgAdisease presenting as desquamative gingivitis: a pattern poorly

recognized in medicine. Arch Otolaryngol Head Neck Surg

2004; 130: 469–72.

61 Rehberger A, Puspok A, Stallmeister T, Jurecka W, Wolf K.

Crohn’s disease masquerading as aphthous ulcers. Eur J

Dermatol 1998; 8: 274–6.

62 Bogenrieder T, Rogler G, Vogt T, Landthaler M, Stolz W.

Orofacial granulomatosis as the initial presentation of Crohn’s

disease in an adolescent. Dermatology 2003; 206: 273–8.

63 Girlich C, Bogenrieder T, Palitzsch KD, Scholmerich J, Lock G.

Orofacial granulomatosis as initial manifestation of Crohn’s

disease: a report of two cases. Eur J Gastroenterol Hepatol

2002; 14: 873–6.

64 Bishop RP, Brewster AC, Antonioli DA. Crohn’s disease of the

mouth. Gastroenterology 1972; 62: 302–6.

65 Tyldesley WR. Oral Crohn’s disease and related conditions. Br

J Oral Surg 1979; 17: 1–9.

66 Gibson J, Neilly JB, Wray AP, Evans TJ, MacKenzie JR,

McKillop JH. [99Tcm]-HMPAO leucocyte labelling in orofacial

granulomatosis and gastrointestinal Crohn’s disease in

childhood and early adulthood. Nucl Med Commun 2000;

21: 155–8.

67 Ficarra G, Cicchi P, Amorosi A, Piluso S. Oral Crohn’s disease

and pyostomatitis vegetans. An unusual association. Oral

Surg Oral Med Oral Pathol 1993; 75: 220–4.

68 Hernandez-Martin A, Arias-Palomo D, Hermida G, et al. Oral

pyoderma gangrenosum. Br J Dermatol 2003; 149: 663–4.

69 Lackey MA, Barth J. Gastroesophageal reflux disease: a dental

concern. Gen Dent 2003; 51: 250–4.

70 Scully C, Beyli M, Ferreiro MC, et al. Update on oral lichen

planus: etiopathogenesis and management. Crit Rev Oral Biol

Med 1998; 9: 86–122.

71 McCartan BE, McCreary CE. Oral lichenoid drug eruptions.

Oral Dis 1997; 3: 58–63.

72 Bratel J, Dahlgren U, Simark MC, Jontell M. The frequency of

different T-cell receptor V-families in oral lichen planus and

lichenoid contact lesions: an immunohistochemical study.

J Oral Pathol Med 1998; 27: 415–9.

73 Nagao Y, Sata M, Ide T, et al. Development and exacerbation

of oral lichen planus during and after interferon therapy for

hepatitis C. Eur J Clin Invest 1996; 26: 1171–4.

74 Hegarty AM, Hodgson TA, Lewsey JD, Porter SR. Fluticasone

propionate spray and betamethasone sodium phosphate

mouthrinse: a randomized crossover study for the treatment

of symptomatic oral lichen planus. J Am Acad Dermatol

2002; 47: 271–9.

75 Kaliakatsou F, Hodgson TA, Lewsey JD, Hegarty AM, Murphy

AG, Porter SR. Management of recalcitrant ulcerative oral

lichen planus with topical tacrolimus. J Am Acad Dermatol2002; 46: 35–41.

76 Porter SR, Scully C, Eveson JW. The efficacy of topical

cyclosporin in the management of desquamative gingivitis

due to lichen planus. Br J Dermatol 1993; 129: 753–5.

77 Rodstrom PO, Jontell M, Mattsson U, Holmberg E. Cancer and

oral lichen planus in a Swedish population. Oral Oncol 2004;

40: 131–8.

78 Silverman S, Bhargava K, Smith LW, Malaowalla AM.

Malignant transformation and natural history of oral

leukoplakia in 57,518 industrial workers of Gujarat, India.

Cancer 1976; 38: 1790–5.

79 Gupta PC, Mehta FS, Pindborg JJ, et al. Intervention study for

primary prevention of oral cancer among 36000 Indian

tobacco users. Lancet 1986; 1: 1235–9.

80 Rajkumar T, Sridhar H, Balaram P, et al. Oral cancer in

Southern India: the influence of body size, diet, infections and

sexual practices. Eur J Cancer Prev 2003; 12: 135–43.

81 Porter S, Scully C. HIV: the surgeon’s perspective: Part 3.

Diagnosis and management of malignant neoplasms. Br J Oral

Maxillofac Surg 1994; 32: 241–7.

82 Lippman SM, Grogan TM, Spier CM, et al. Lethal midline

granuloma with a novel T-cell phenotype as found in

peripheral T-cell lymphoma. Cancer 1987; 59: 936–9.

83 Scully C, Bagan JV. Adverse drug reactions in the orofacial

region. Crit Rev Oral Biol Med 2004; 15: 221–39.

306 S . R . P O R TE R & J. C. LE A O


oral ulceration and its relevance to systemic disorder

Documents