A guide to oral ulceration for the medical physician

Ulserasi oral adalah temuan umum namun klasifikasi, diagnosis dan manajemennya tetap
menjadi tantangan bagi banyak dokter rumah sakit. Artikel ini membahas berbagai jenis ulserasi
mulut dan bagaimana cara menginvestigasi dan mengelolanya.

The clinical presentation of oral ulcers is varied, reflecting the diverse aetiological processes that
can be involved in their development. However, all ulcers represent a breach in the epithelium
that extends to the underlying lamina propria. In contrast, erosions are more superficial lesions,
where there is an incomplete break in the epithelium which does not extend to the underlying
connective tissue.

Oral ulceration may arise entirely in isolation or in combination with systemic features. A
thorough history, in conjunction with appropriate clinical examination, is vital to reach the
correct diagnosis and thus enable appropriate management. In particular, it is important to
distinguish between recurrent and non-recurrent ulceration as this guides further investigations
and management.

Assessment of oral ulceration

History
The history should consist of a detailed description of the ulceration, in addition to a thorough
medical and family
history (Table 1) (Paleri et al, 2010; Le Doare et al, 2014). Physicians should be aware that
commonplace non-specific use of the term ‘ulcer’ may result in patients using this word to
describe erosions, ulcers, erythema,
blisters or other soft tissue pathology.

Examination
All mucosal surfaces within the oral cavity should be examined, noting site(s), size, number,
consistency and
the presence of cervical lymphadenopathy. Dental appliances should also be examined. If the
clinical history
raises suspicion, a full dermatological, ocular and genital examination may also be required.

Classification of oral ulcers

Causes of oral ulceration can be broadly categorized as follows (Le Doare et al, 2014):
 Local
 Drugs
 Recurrent aphthous stomatitis
 Malignant
 Systemic disease.
Local causes
Trauma is a common cause of oral ulceration with orthodontic appliances, dentures and fractured
teeth liable to injure the oral mucosa. Ulceration is usually solitary with an obvious identifiable
cause and referral to the patient’s dentist may be required to assist with adjustment to teeth or
dental appliances. Traumatic ulceration may also be a result of thermal and chemical causes
(Hullah and Hegarty, 2014). Removal of the aetiological factor should result in healing of the
ulcer(s) and topical analgesia (benzydamine hydrochloride mouthrinse or spray) can be a useful
adjunct. All patients with persistent or non-healing lesions should be referred for specialist
assessment in secondary or tertiary care (oral medicine or oral and maxillofacial services).

Drugs
Potentially, many drugs can cause oral ulceration with the clue to identifying the cause being a
temporal relation between drug initiation and improvement of symptoms upon drug withdrawal.
The precise mechanism of injury is not always clear and common culprits include: labetalol,
alendronate, captopril, nicorandil, non-steroidal anti-inflammatory drugs, mycophenolate
mofetil, methotrexate, protease inhibitors and tacrolimus (Scully and Bagan, 2004). Figure 1
shows an ulcer which developed as a result of a patient taking methotrexate.
Stevens–Johnson syndrome is a rare form of toxic epidermal necrolysis characterized by severe
ulceration of less than 10% of the total body area affecting the oral cavity, skin and other mucous
membranes (Gerull et al, 2011). There are many potential medications that can cause this
syndrome. Treatment is usually supportive with withdrawal of the offending agent, although
immunosuppressant therapy may be required for more severe cases.

Recurrent aphthous stomatitis

Recurrent aphthous stomatitis is synonymous with recurrent aphthous ulceration and is the most
common cause of recurrent oral ulceration. This idiopathic condition is characterized by
recurrent episodes of oral ulceration in the absence of additional oral or systemic features, with
diagnosis primarily based on exclusion of other causes of recurrent ulceration. Recurrent
aphthous stomatitis is common in the general population with prevalence estimates between 5
and 60% (Brocklehurst et al, 2012) and 25% of the general population affected at some time
(Scully, 2006). Its aetiology is poorly understood but is likely to be multifactorial including
genetic and environmental susceptibility factors.
Recurrent aphthous stomatitis is sub-classified into three types, primarily by size:
 Minor recurrent aphthous stomatitis (75–85% of cases). Typically crops of 1–6 ulcers, <1
cm diameter, which heal within 1–2 weeks without scarring (Figure 2)
 Major recurrent aphthous stomatitis (10–15% of cases). Crops of 1–3 ulcers, usually >1
cm diameter, which heal within 2–4 weeks and cause scarring
 Herpetiform (rare). Crops of small (0.5–3 mm) ulcers which tend to coalesce. These heal
within 1–2 weeks without scarring.

Initial investigations include routine blood tests for anaemia and haematinic deficiency. Topical
benzydamine hydrochloride can be used for symptom relief, but patients often require active
treatment, with topical steroids (e.g. soluble betamethasone) being the first line. For recalcitrant
cases, systemic therapies such as colchicine or immunosuppressants (e.g. azathioprine,
mycophenolate mofetil, thalidomide) may be required.

Malignant ulcers
Any non-healing oral ulcer present for 2 weeks or more should be treated as suspicious for
malignancy. Malignant oral ulcers are most commonly squamous cell carcinomas. Rarer causes
include lymphomas, salivary gland tumours and Kaposi’s sarcoma, but breast, lung and prostate
cancer can also metastasize to the oral cavity. Most oral malignancy arises de novo although
some malignant neoplasms may arise in the context of potentially malignant lesions or
conditions, such as erythroplakia, leukoplakia, submucous fibrosis, oral lichen planus and
discoid lupus erythematosus.

Squamous cell carcinoma

Squamous cell carcinoma is the most common malignancy of the oral cavity and risk factors
include tobacco use, betel use and excessive alcohol consumption (Warnakulasuriya, 2009).
Squamous cell carcinoma may present as an ulcer and is typically solitary and indurated with a
rolled margin. Cervical lymphadenopathy may be an associated feature. Patients presenting with
ulceration suspicious of malignancy should be referred as part of the cancer 2-week pathway to
local oral medicine or oral and maxillofacial surgery services for urgent investigation (typically
incisional biopsy) and management, most commonly surgery and/or radiotherapy.

Systemic diseases
There are many systemic conditions that can be associated or present with oral ulceration,
including infections (bacterial, viral and fungal), haematological, dermatological, gastrointestinal
and inflammatory disorders.

Infectious causes of oral ulceration

Herpes group viruses: Herpes simplex virus is the most common viral infection to affect the
oral cavity. Primary infection with herpes simplex virus type 1 (HSV-1) (primary herpetic
gingivostomatitis) typically occurs in early childhood and is often confused with teething,
although a second peak is observed in the early twenties (Arduino and Porter, 2008). Infection
presents as a single episode of widespread oral vesicles, which rupture to form shallow painful
ulcers with associated lymphadenopathy. The infection is selflimiting, resolving after 10–14
days. Diagnosis is made on the basis of clinical presentation and history, with supportive
treatment comprising analgesics, soft diet and prevention of secondary infection (chlorhexidine
mouthwash).
Approximately 20–40% of previously infected individuals develop reactivation of the
dormant infection in the trigeminal ganglion (Woo and Challacombe, 2007). This most
commonly presents as herpes labialis (cold sores) although intra-oral involvement can occur,
causing vesicles that ulcerate in one branch of the trigeminal nerve. Supportive treatment is
usually sufficient, although topical agents or systemic antivirals (aciclovir or valaciclovir)
may be indicated in some cases.
Varicella-zoster virus rarely affects the mouth. Reactivation of varicella-zoster virus presents in a
similar manner to that of herpes simplex, although it is often more painful and there is a risk of
post-herpetic neuralgia. Treatment is supportive with the addition of systemic antivirals
(aciclovir, valaciclovir or ganciclovir) for more severe cases as this may help reduce the risk of
postherpetic neuralgia. Ocular involvement should prompt urgent referral to the local
ophthalmology services.
Coxsackie virus: Coxsackie viruses can cause herpangina (group A coxsackie) and hand, foot
and mouth (coxsackievirus A16), with both conditions typically affecting children. Herpangina
presents with widespread small ulcers with associated fever and malaise. The presentation is
similar to primary herpes simplex but there is no gingival involvement and the posterior oral
cavity is the main site. The infection Is self-limiting and usually resolves within 14 days. Hand,
foot and mouth is characterized by a popular rash which develops on the hands and feet with oral
vesicles that rupture to cause oral ulceration. It rarely affects the gingivae. The infection is self-
limiting and resolves after 10–14 days.

HIV: Oral ulceration associated with human immunodeficiency virus (HIV) can present in many
ways, usually with non-specific aphthous-like ulceration. Increased susceptibility to infections
can cause bacterialand fungal-related oral ulceration, in addition to ulcers associated with the
reactivation of herpes virus. Neoplastic ulcers, e.g. ulcerated Kaposi’s sarcoma or lymphoma,
may arise.

Tuberculosis: Tuberculosis is caused by infection with Mycobacterium tuberculosis. Its

worldwide incidence has risen in recent years, particularly in the immunocompromised and
immigrant populations. Oral involvement is rare but can present as a deep painful ulcer with
raised margins usually on the posterior tongue. The diagnosis is confirmed by biopsy with
positive Ziehl–Neelsen staining revealing mycobacterium. Patients require referral to chest
medicine for multidisciplinary management with appropriate anti-tuberculosis treatment.

Syphilis: Syphilis is caused by Treponema pallidum infection and can affect the mouth in any of
its three phases. Primary syphilis presents as a painless ulcerated nodule (chancre) at the site of
inoculation. At this stage it is highly infectious and typically resolves within 1–2 months.
Secondary syphilis develops approximately 2 months after the primary lesion has healed and can
affect the mouth regardless of the site of primary infection. It presents as superficial grey
sloughing ulcers, classically described as snail-track ulcers, which resolve and recur. Tertiary
syphilis develops many years later characterized by marked necrotic granulomatous reactions
termed gumma. These typically affect the palate and tongue and may enlarge and ulcerate.
Multidisciplinary management is required and patients should be referred to the department of
genitourinary medicine for assessment and administration of depot penicillin.

Fungal infections: Deep mycoses are fungal infections caused by inhalation of fungal spores
present in soil. They are endemic to certain parts of the world, particularly South America. They
include Histoplasma, Cryptococcus and Aspergillus. They commonly affect
immunocompromised patients and those who have travelled to endemic areas. Clinically they
present as persistent solitary oral ulcers. Treatment requires referral to specialist physicians and
systemic antifungals.

Haematological disorders
Anaemia secondary to iron, vitamin B12 or folate deficiency or anaemia of chronic disease can
cause recurrent oral ulceration that resembles recurrent aphthous stomatitis. Management
requires haematinic replacement therapy, although improvement in ulceration is not always seen.
Further management is similar to that of recurrent aphthous stomatitis.
There are a number of other haematological disorders that may cause oral ulceration:
 Neutropenia, where oral ulcers characteristically lack an erythematous halo
 Leukaemia
 Lymphoma (e.g. non-Hodgkin lymphoma can present as a swelling of the pharynx,
tongue, gingivae and lip which can then ulcerate).

Dermatological disorders
Vesicullobullous conditions: Mucous membrane pemphigoid and pemphigus vulgaris can affect
the oral cavity. Both are autoimmune conditions with antibodies produced against either
hemidesmosones (pemphigus) or desmosomes (pemphigoid). Clinically, bullae (blisters) appear
on the oral mucosa, which rupture to leave ragged ulceration and erosions. Some patients may
experience desquamative gingivitis (Figure 3), with a characteristic erythematous appearance of
the gingivae. If suspected, the patient should be referred urgently to local oral medicine services
for confirmation with immunofluorescence. Management requires a multidisciplinary approach
with dermatology and ophthalmology. Although disease severity may vary greatly, many
patients require long-term systemic immunosuppressant therapy.

Lichen planus: Lichen planus is a mucocutaneous disorder of likely autoimmune aetiology.

There is a wide spectrum of clinical features but oral lichen planus classically presents with
white striae of the mucosa, known as Wickham’s striae (Figure 4). Mucosal erosions and
ulceration may occur with considerable associated morbidity. Patients require referral to oral
medicine with possible additional dermatology management. Topical steroids are usually
successful, but some patients require systemic immunosuppression.

Gastroenterological disorders
A number of gastrointestinal conditions are associated with oral ulceration:

Coeliac disease (gluten-sensitive enteropathy): Coeliac disease is an autoimmune disorder

resulting in a hypersensitivity to gluten and subsequent villous atrophy in the small intestine.
Patients may develop systemic features of malabsorption and weight loss. The oral
manifestations include oral ulcers, angular cheilitis and rarely glossitis. Screening is performed
with serological blood tests (anti-tissue transglutaminase antibodies) and small bowel biopsy is
the diagnostic gold standard. Treatment consists of a lifelong gluten-free diet. Associated oral
ulceration is treated in a similar manner to recurrent aphthous stomatitis.

Orofacial granulomatosis and Crohn’s disease:

Orofacial granulomatosis and Crohn’s disease are granulomatous inflammatory conditions: while
orofacial granulomatosis is restricted to the orofacial region, Crohn’s disease affects any part of
the gastrointestinal tract, most commonly the terminal ileum. They are likely to be distinct
separate diseases which share common histological features and have thus become historically
linked. Orofacial granulomatosis usually exists as a distinct orofacial entity although a
significant proportion of patients also have concurrent intestinal Crohn’s disease (Campbell et al,
2011).
The precise aetiologies of orofacial granulomatosis and Crohn’s disease are unknown but
are likely to be caused by environmental factors in genetically susceptible hosts. Interestingly,
allergy has been shown to be strongly associated with orofacial granulomatosis and to a lesser
extent, with Crohn’s disease (Patel et al, 2013). Orofacial suggranulomatosis commonly presents
with intermittent lip swelling and oral ulceration, usually in the buccal sulcus (Figure 5). The
ulceration can be deep seated and in rare situations can penetrate the oral mucosa resulting in
orofacial fistulae (Shah et al, 2014). The clinical features of orofacial granulomatosis are listed in
Table 2. The oral manifestations of Crohn’s disease are usually the result of haematinic
malabsorption.
Specific management varies depending on disease severity and the sites affected. Certain
food stuffs are known to trigger symptoms in a large proportion of patients with orofacial
granulomatosis and these patients may respond to a cinnamon- and benzoate-free diet under the
guidance of a specialist dietician (Campbell et al, 2013). Both topical and systemic steroids,
immunosuppressants and biologic therapy may be used for patients with orofacial
granulomatosis or Crohn’s disease. Surgery (cheiloplasty) is reserved for patients with the most
severe cases of orofacial granulomatosis or once medical therapy has failed in burntout disease.
KEY POINTS
 Minor ulceration can be initially managed with supportive treatment, but persistent or
recurrent ulceration should be referred to oral medicine services for further investigation
and management.
 Recurrent aphthous stomatitis is a common cause of ulceration and is often a diagnosis of
exclusion.
 The aetiology and presentation of ulcers varies greatly and a thorough history and
examination are required to allow appropriate management.
 Ulcers may be associated with a systemic disease which may require multidisciplinary
investigations and management.
 Initial management of ulceration is with topical steroids although severe cases may
require systemic immunomodulation.
 It is crucial to detect malignant conditions which require urgent referral and
treatment.

Ulcerative colitis: Ulcerative colitis is an inflammatory bowel disease of unknown aetiology that
affects the colon. However, oral manifestations of disease can arise including non-specific oral
ulceration and, rarely, mucosal pustules (pyostomatitis vegetans). The management is similar to
Crohn’s disease with early use of immunosuppressant medications.
Behçet’s disease
Behçet’s disease is a rare multisystem inflammatory disease likely to be of autoimmune
vasculitic aetiology. Classically, it presents in a relapsing and remitting fashion as a triad of oral
and genital ulceration with uveitis. However, there are a variety of other manifestations including
cutaneous lesions, as well as joint and neurological symptoms. The diagnosis is based on clinical
history and examination. Oral ulcers appear similar to those of recurrent aphthous stomatitis
(Figure 6). Patients suspected of having Behçet’s disease should be referred to a specialist
rheumatology or oral medicine unit. Patients often require systemic treatment with a broad range
of immunosuppressive therapies used depending on clinical features.

Conclusions
This article outlines the different causes of oral ulceration. A thorough history and clinical
examination is crucial and patients with persistent or recurrent ulceration should be referred for
specialist treatment. A sug gested investigation pathway is history (including trauma, drugs and
systemic features), examination (which should include the oral cavity, dermatological system,
genitourinary system and gastrointestinal system) and investigations (including bloods: serum
angiotensinconverting enzyme, full blood count, C-reactive protein, haematinics, HIV, biopsy
and any other specific system investigations which may become necessary, e.g.colonoscopy).