DOI: 10.1111/prd.
12262
REVIEW ARTICLE
Recurrent oral ulceration: Etiology, classification, management,
and diagnostic algorithm
Elizabeth A. Bilodeau1 | Rajesh V. Lalla2
1
Department of Diagnostic Sciences, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, USA
2
Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, USA
Correspondence
Rajesh V. Lalla, Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, CT.
Email: Lalla@uchc.edu
1 | I NTRO D U C TI O N
Owing to the anatomic location, rich vasculature, and various func-
tions of the oral cavity, the oral mucosa is exposed to a variety of
insults. These include trauma from chewing or oral appliances, local
irritation secondary to foods/drugs, exposure to systemically in-
gested drugs (through the blood supply), infectious agents, and ef-
fects of autoimmune and other systemic diseases. These insults can
result in a variety of oral manifestations, ranging from hyperkerato-
sis to lichenoid lesions to frank ulceration. This review will discuss
the etiology, pathogenesis, diagnosis, and management of the more
common conditions that can lead to recurrent oral ulceration.
2 | TR AU M ATI C U LC E R ATI O N
The oral cavity is subjected to many sources of potential physical
trauma. The most common is trauma from cheek-­biting during chew-
ing. Such frictional trauma may result in a white hyperkeratotic le-
sion due to production of excess keratin by the oral epithelial cells
or in frank ulceration, which can be recurrent if the trauma per-
sists. Such lesions are more likely on the buccal mucosa adjacent to
the site where the teeth occlude and may be subject to repeated
trauma. Diagnostic indicators may include lesions in a trauma-­prone
site, patient history, appearance of tissue getting caught between
teeth, and presence of sharp or fractured cusps on adjacent teeth
(Figure 1). Another common source of recurrent oral trauma is from
ill-­fitting appliances, sharp clasps, or tongue piercings. Certain foods
may also cause trauma; for example, a sharp potato chip or hot pizza
can lead to palatal ulceration; however, such injuries tend not to be
recurrent. Some patients may have a subconscious habit of chewing
on the lip or buccal mucosa (morsicatio labiorum or morsicatio buc-
carum), which usually results in a hyperkeratotic lesion but can cause
ulceration; the injuries are sometimes deliberate, representing what
Periodontology 2000. 2019;80:49–60. wileyonlinelibrary.com/journal/prd
is known as factitious injury. Reduced salivary flow (secondary to
drugs or disease) can predispose to recurrent traumatic injury due to
the loss of the lubricating effect of saliva.
Management involves elimination of the source of trauma, such
as rounding of sharp cusps. Patients with dry mouth can be pre-
scribed sialagogues, such as pilocarpine (5 mg tid), which has been
shown to increase salivary flow.1 Over-­the-­counter products such
as salivary substitutes, mouthwashes, and moisturizing gels are also
available (eg, Biotene Oralbalance or Gum Hydral products) and can
provide symptomatic relief to some patients. 2
3 | C H E M I C A L U LC E R ATI O N
Topical chemical injury to the oral mucosa can result in oral ulcera-
tion. Although this is not usually recurrent in the majority of patients,
repeated use of the offending agent may result in recurrence of ul-
cers. Keeping aspirin or other systemic medications in the mouth can
result in tissue burn, necrosis, and ulceration. Rinsing with a high
concentration of hydrogen peroxide can also lead to chemical injury.
A careful history may reveal the cause, such as rinsing or topical ap-
plication of a caustic chemical. Chemical ulcerations may also be iat-
rogenic in nature, with a history of recent dental treatment (Figure 2)
involving materials such as formocresol or sodium hypochlorite. Use
by the patient or provider of tooth-­whitening products can also re-
sult in soft tissue damage if applied improperly.3 Chemical irritants
can cause direct damage to oral epithelium due to their acidic or al-
kaline nature. They cause coagulative necrosis of the mucosa, lead-
ing to oral ulceration.4
Management of these lesions includes identification and elimina-
tion of the source of ulceration. Primary clinical care is supportive in
nature, including pain management with coating mouth rinses (com-
mon ingredients of these solutions include viscous lidocaine, alumi-
num hydroxide [Maalox], and diphenhydramine [Benadryl]).
© 2019 John Wiley & Sons A/S. | 49
Published by John Wiley & Sons Ltd
50 | BILODEAU and LALLA
4 | R ECU R R E NT A PHTH O U S S TO M ATITI S
Recurrent aphthous stomatitis, also known as aphthous ulcers or
canker sores, is the most common oral mucosal disease in humans
in all geographic regions. 5 Embil et al conducted a comprehensive
prospective questionnaire survey on the prevalence of recurrent
aphthous stomatitis involving over 10 000 young adults in 21 dif-
ferent countries.6 In that study, 38.7% of men and 49.7% of women
self-­reported having two or more previous occurrences of recur-
rent aphthous stomatitis. Approximately 25% of the participants
reported at least one episode of recurrent aphthous stomatitis dur-
ing the past 1 year.6 Recurrent aphthous stomatitis is seen most
commonly in younger patients, with a peak onset between 10 and
5,7
29 years of age. Ulcers are disproportionately painful for their
size, and three forms of recurrent aphthous stomatitis have been
described: major, minor, and cluster form (sometimes misleadingly
referred to as herpetiform).
Although several predisposing factors have been hypothesized,
the exact pathogenesis of recurrent aphthous stomatitis is still
poorly understood. The most commonly implicated etiologies are as
follows:
FIGURE 1 A traumatic ulcer adjacent to a fractured tooth with
sharp edges
FIGURE 2 Chemical burn from extensive exposure of the mucosa to monomer in provisional bridge. Lesion is associated with pain
1. Genetic factors. There is a genetic component in patients with
aphthous ulcers, with about 30%-40% of patients having a
family history.7 Various genetic polymorphisms have been linked
to recurrent aphthous stomatitis. A polymorphism of the cell
adhesion molecule E-selectin was found to be approximately
10 times more common in patients with recurrent aphthous
stomatitis compared with controls; this may affect susceptibility
by promoting leukocyte accumulation and invasion of the ep-
ithelium.8 Another study found a significant increase in a poly-
morphism of Toll-like receptor 4 in recurrent aphthous stomatitis
patients; this is an essential component of innate immunity
and the cellular immune response.9
2. Stress. There is a strong association of recurrent aphthous stoma-
titis occurrences with stressful life events. A study of 160 recur-
rent aphthous stomatitis subjects (mean age 36.03 years, 65%
female) followed for 1 year reported that experiencing a stressful
life event increased the odds of a recurrent aphthous stomatitis
episode by almost three times (odds ratio [OR] = 2.72; 95% confi-
dence interval [CI] = 2.04-3.62). When controlled for each other,
psychological stressors (such as an examination or job interview)
had a larger effect (OR = 3.46, 95% CI = 2.54-4.72) than physical
stressors (such as a physical illness or injury) (OR = 1.44; 95%
CI = 1.04-1.99) on the occurrence of recurrent aphthous stomati-
tis episodes.10
3. Nutritional deficiency. Various nutritional deficiencies have been
implicated in a subset of recurrent aphthous stomatitis patients,
including those of iron, folic acid and vitamin B12. The contribu-
tion of nutritional deficiencies to recurrent aphthous stomatitis
likely varies across different regions based on diet and food sup-
plementation. For example, a review of studies indicated that 0%-
42% of recurrent aphthous stomatitis patients were reported to
have a deficiency of vitamin B12. This is a large range, but it indi-
cates the geographical variability of nutritional deficiency as a
contributing factor.11 One study has also reported that vitamin
B12 supplementation may be beneficial in recurrent aphthous sto-
matitis, regardless of initial blood B12 level.12
Minor aphthous ulcers represent about 80% of all aphthous ul-
cers and are seen most commonly on the nonkeratinized oral mu-
cosa, including the labial mucosa, buccal mucosa, and ventral surface
BILODEAU and LALLA
of the tongue.13 They are usually less than 1 cm in size (4-­6 mm).
They are characterized by a round to oval area of ulceration with a
yellowish fibrin coating, surrounded by a ring of erythema (Figure 3).
They usually heal without scarring within 7-­10 days.
Major aphthous ulcers are larger, measuring over 1 cm in size.
They can take 4-­6 weeks to heal and may have resultant scarring.
Clusterform ulcers are uncommon, presenting as a cluster of 10-­100
oral ulcers, each 2-­3 mm in size. Lesions may coalesce, leading to
larger, irregular ulcers. They usually heal in 10-­14 days.
Diagnosis of aphthous ulceration is usually made on clinical ap-
pearance and history of duration and recurrence. Histology is non-
specific, showing a surface layer consisting of a fibrinous exudate
infiltrated by polymorphonuclear leukocytes, ulceration of epithe-
lium, and inflammation extending deeply. Hematological investiga-
tions to rule out deficiencies should be performed for cases that do
not fit the typical pattern in terms of patient profile, frequency of
episodes, or duration of lesions. These can include testing for de-
10,14,15
ficiencies of vitamin B12, iron, and folate. Onset of aphthous
ulcers in the third decade of life or later is uncommon. If this occurs,
ulceration associated with systemic disease should be considered
(see Autoimmune/systemic diseases with associated ulceration,
Section 8).
Minor aphthous ulcers with mild symptoms usually do not re-
quire specific treatment. Local measures, such as the use of salt
water mouth rinses, may be sufficient until the ulcers heal sponta-
neously. When the ulcers become bothersome and painful, treat-
ment is indicated and is often sought by frustrated patients. The
mainstay of therapy is application of topical steroids. Commonly
used agents include triamcinolone acetonide (available as Kenalog
in Orabase for direct application to the lesions, although availability
of this product may be limited in some locations) and dexametha-
sone elixir (used as a mouthwash). Intralesional injection of steroids
may also be used for painful, large lesions. In some cases, systemic
therapy with steroids or other agents may be necessary in the short
term. A recent Cochrane review of systemic treatments for recurrent
aphthous stomatitis included 25 trials and found that no single agent
F I G U R E 3 Recurrent aphthous ulcer located on the
ventrolateral tongue. A tan-­yellow ulceration is seen with an
erythematous border
| 51
was effective, and the results remained inconclusive.16 Commonly
studied agents are listed in Table 1.
5 | M E D I C ATI O N - ­R E L ATE D U LC E R ATI O N
Numerous systemic medications used in oncology, rheumatology,
and transplant medicine have the ability to induce significant oral
ulceration, some of which may be recurrent.
Oral mucositis is a common side effect of a number of conventional
chemotherapy agents, such as 5-­fluorouracil, docetaxel, and doxoru-
bicin.17 Ulcerative oral mucositis secondary to such drugs presents
as diffuse oral ulcers that arise after administration of chemotherapy
and usually heal within a few weeks after cessation of chemotherapy
(Figure 4). Lesions tend to recur with succeeding cycles of chemother-
apy. The pathogenesis of oral mucositis is complex and includes direct
damage to basal epithelial cells from the chemotherapeutic agent, up-
regulation of proinflammatory factors, such as nuclear factor kappa B
and tumor necrosis factor alpha, and further damage due to products
of colonizing microflora.18 Evidence-­based clinical practice guidelines
for oral mucositis support the use of basic oral care, oral cryotherapy
(ice chips), keratinocyte growth factor-­1 (palifermin), and low-­level
laser therapy for chemotherapy-­induced oral mucositis, each in spe-
cific patient populations.19 The detailed guidelines, along with the
level of evidence for each, are presented in Table 2.
TA B L E 1 Commonly studied agents for the management of
recurrent aphthous stomatitis
Topical agents Systemic agents
Triamcinolone acetonide in Orabase Prednisone
Doxycycline Colchicine
Minocycline Levamisole
Amlexanox Vitamins (including
vitamin B12)
Laser therapy
F I G U R E 4 Chemotherapy-­induced oral mucositis present on
the buccal mucosa. Diffuse irregular erythema with focal mucosal
sloughing is seen
52 | BILODEAU and LALLA

TA B L E 2 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology evidence-­based clinical practice
guidelines for oral mucositis secondary to cancer therapy

RECOMMENDATIONS IN FAVOR OF AN INTERVENTION (ie, strong evidence supports effectiveness in the treatment setting listed)
1. The panel recommends that 30 min of oral cryotherapy be used to prevent oral mucositis in patients receiving bolus 5-fluorouracil chemother-
apy (Level of Evidence II).
2. The panel recommends that recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) be used to prevent oral mucositis (at a dose of
60 μg/kg/d for 3 d prior to conditioning treatment and for 3 d posttransplant) in patients receiving high-dose chemotherapy and total body
irradiation, followed by autologous stem cell transplantation, for a hematological malignancy (Level of Evidence II).
3. The panel recommends that low-level laser therapy (wavelength at 650 nm, power of 40 mW, and each square centimeter treated with the
required time to a tissue energy dose of 2 J/cm2), be used to prevent oral mucositis in patients receiving hematopoietic stem cell transplantation
conditioned with high-dose chemotherapy, with or without total body irradiation (Level of Evidence II).
4. The panel recommends that patient-controlled analgesia with morphine be used to treat pain due to oral mucositis in patients undergoing
hematopoietic stem cell transplantation (Level of Evidence II).
5. The panel recommends that benzydamine mouthwash be used to prevent oral mucositis in patients with head and neck cancer receiving
moderate-dose radiation therapy (up to 50 Gy), without concomitant chemotherapy (Level of Evidence I).
SUGGESTIONS IN FAVOR OF AN INTERVENTION (ie, weaker evidence supports effectiveness in the treatment setting listed)
1. The panel suggests that oral care protocols be used to prevent oral mucositis in all age groups and across all cancer treatment modalities (Level
of Evidence III).
2. The panel suggests that oral cryotherapy be used to prevent oral mucositis in patients receiving high-dose melphalan, with or without total body
irradiation, as conditioning for hematopoietic stem cell transplantation (Level of Evidence III).
3. The panel suggests that low-level laser therapy (wavelength around 632.8 nm) be used to prevent oral mucositis in patients undergoing
radiotherapy, without concomitant chemotherapy, for head and neck cancer (Level of Evidence III).
4. The panel suggests that transdermal fentanyl may be effective to treat pain due to oral mucositis in patients receiving conventional or high-dose
chemotherapy, with or without total body irradiation (Level of Evidence III).
5. The panel suggests that 0.2% morphine mouthwash may be effective to treat pain due to oral mucositis in patients receiving chemoradiation for
head and neck cancer (Level of Evidence III).
6. The panel suggests that 0.5% doxepin mouthwash may be effective to treat pain due to oral mucositis (Level of Evidence IV).
7. The panel suggests that systemic zinc supplements administered orally may be of benefit to prevent oral mucositis in oral cancer patients
receiving radiation therapy or chemoradiation (Level of Evidence III).
RECOMMENDATIONS AGAINST AN INTERVENTION (ie, strong evidence indicates lack of effectiveness in the treatment setting listed)
1. The panel recommends that PTA (polymyxin, tobramycin, amphotericin B) and BCoG (bacitracin, clotrimazole, gentamicin) antimicrobial
lozenges and PTA paste not be used to prevent oral mucositis in patients receiving radiation therapy for head and cancer (Level of evidence II).
2. The panel recommends that iseganan antimicrobial mouthwash not be used to prevent oral mucositis in patients receiving high-dose chemo-
therapy, with or without total body irradiation, for hematopoietic stem cell transplantation (Level of Evidence II), or in patients receiving
radiation therapy or concomitant chemoradiation for head and neck cancer (Level of Evidence II).
3. The panel recommends that sucralfate mouthwash not be used to prevent oral mucositis in patients receiving chemotherapy for cancer (Level of
Evidence I), or in patients receiving radiation therapy (Level of Evidence I) or concomitant chemoradiation (Level of Evidence II) for head and
neck cancer.
4. The panel recommends that sucralfate mouthwash not be used to treat oral mucositis in patients receiving chemotherapy for cancer (Level of
Evidence I), or in patients receiving radiation therapy (Level of Evidence II) for head and neck cancer.
5. The panel recommends that intravenous glutamine not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, with or
without total body irradiation, for hematopoietic stem cell transplantation (Level of Evidence II).
SUGGESTIONS AGAINST AN INTERVENTION (ie, weaker evidence indicates lack of effectiveness in the treatment setting listed)
1. The panel suggests that chlorhexidine mouthwash not be used to prevent oral mucositis in patients receiving radiation therapy for head and
neck cancer (Level of Evidence III).
2. The panel suggests that granulocyte macrophage colony-stimulating factor mouthwash not be used to prevent oral mucositis in patients
receiving high-dose chemotherapy, for autologous or allogeneic stem cell transplantation (Level of Evidence II).
3. The panel suggests that misoprostol mouthwash not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck
cancer (Level of Evidence III).
4. The panel suggests that systemic pentoxifylline, administered orally, not be used to prevent oral mucositis in patients undergoing bone marrow
transplantation (Level of Evidence III).
5. The panel suggests that systemic pilocarpine, administered orally, not be used to prevent oral mucositis in patients receiving radiation therapy
for head and neck cancer (Level of evidence III), or in patients receiving high-dose chemotherapy, with or without total body irradiation, for
hematopoietic stem cell transplantation (Level of Evidence II).

Newer, targeted agents for cancer have also been reported to
result in oral ulceration. For example, mammalian target of rapa-
mycin inhibitors such as everolimus and temsirolimus result in
ulcerative stomatitis in 40%-­80% of patients. Unlike mucositis sec-
ondary to conventional chemotherapy, mammalian target of rapa-
mycin inhibitor-­associated stomatitis presents as small aphthous-like
ulcers. 20 Some case series have suggested that these lesions are
responsive to topical and systemic steroid therapy. 21 A recent mul-
ticenter study in breast cancer patients receiving everolimus and ex-
emestane reported that dexamethasone mouthwash (0.5 mg/5 mL)
used prophylactically substantially reduced the incidence and fre-
quency of stomatitis compared with a historical control group. 22
BILODEAU and LALLA | 53

Methotrexate is an antimetabolite used in the treatment of TA B L E 3 Human herpes viruses

malignancy as well as in autoimmune diseases such as rheumatoid
Human
arthritis due to its anti-­inflammatory properties. High doses of herpes Most common oral
methotrexate, defined as greater than 1 g/m2 in adults, are used virus Synonym manifestation
in oncologic treatments in chemotherapy protocols, with toxicities HHV-­1 Herpes simplex Oral/genital herpes, “cold sores”
including mucocutaneous ulceration, nausea, vomiting, nephro- virus 1
toxicity, hepatotoxicity, and myelosuppression. 23-25 Methotrexate HHV-­2 Herpes simplex Oral/genital herpes, “cold sores”
can directly result in oral ulceration; furthermore, Epstein-­B arr virus 2
virus–positive mucocutaneous ulcers have also been reported in HHV-­3 Varicella zoster Chicken pox & herpes zoster
patients taking methotrexate, 26 and lymphomata can develop. virus (shingles)
Mycophenolate mofetil is an immunosuppressant used in con- HHV-­4 Epstein-­Barr virus Oral hairy leukoplakia &
junction with other medications with immunosuppressant qualities, Epstein-­Barr virus–positive
mucocutaneous ulcers , oral
including calcineurin inhibitors and steroids. There have been re-
lympomas
cent reports of mycophenolate-­
mofetil-­
induced oral ulceration in
HHV-­5 Cytomegalovirus Oral ulceration
transplant patients that have resolved with cessation of the drug.27
HHV-­6 Roseolovirus No oral manifestation
Replacement of the drug with azathioprine may allow the oral lesions
28 HHV-­7 Roseolovirus No oral manifestation, similar to
to resolve.
HHV-­6, associated with
Other medications, such as piroxicam, naproxen, losartan, and pityriasis rosea
trimethoprim-­sulfamethoxazole, have also been implicated in caus- HHV-­8 Kaposi’s sarcoma-­ Kaposi’s sarcoma
ing oral ulcers. 29 Of these, the nonsteroidal anti-­inflammatory drugs associated
are most commonly implicated. Possible mechanisms involved in- herpesvirus
clude a reduction in mucoprotective prostaglandins due to cycloo-
xygenase inhibition and the vasoconstrictive effect of nonsteroidal acyclovir, valacyclovir, penciclovir, and famciclovir).34,35 Limitations
anti-­inflammatory drugs, which reduces blood flow and results in exist in the research, with available randomized trials limited and
hypoxia.30 Sulfonamides can trigger oral ulcerations associated with small sample sizes, but pediatric patients with primary herpetic gin-
erythema multiforme (discussed later). givostomatitis taking acyclovir have been shown to have lesions heal
faster with other clinical improvements, such as diminished fever,
less pain and less discomfort on eating and drinking.36-38 Decreased
6 | I N FEC TI O U S U LC E R ATI O N fluid intake or dehydration is a common associated sequela. Rare
complications of the infection include herpes simplex virus-related
A variety of viral or, less commonly, bacterial pathogens can result keratitis and blepharitis, characterized by small branching epithelial
in oral ulceration. Recurrent intraoral ulceration of an infectious na- dendrites on the surface of the cornea, which may lead to blindness,
ture is not common in immunocompetent patients but may be seen and encephalitis; thus, special consideration for treatment should
with the pathogens briefly discussed in the following. Please refer to be given to immunocompromised patients.35,39,40 Herpes simplex
chapter 10 for a more comprehensive discussion of viral, bacterial, virus related keratitis results from reactivation of the virus within
and fungal infections. the trigeminal ganglion and has been estimated to affect 50 000 pa-
Herpes simplex virus types 1 and 2 are members of the tients in the United States with new or recurrent ocular disease an-
Herpesviridae family (Table 3). More than 85% of the population nually.41 Ninety percent of encephalitis is caused by herpes simplex
worldwide has been infected with these as they are easily trans- virus type 1 and most commonly seen in patients less than 3 years
mitted through bodily secretions, including saliva.31 Herpes simplex old, with a second smaller peak in patients over 50 years of age.
virus type 1 is the causative organism in most cases of virus-­induced Herpes simplex virus is thought to access the central nervous sys-
recurrent oral ulceration. However, with oral-­genital contact, her- tem via retrograde travel along the trigeminal and olfactory nerves,
pes simplex virus type 2 may also be implicated in oral lesions. although it is unclear whether central nervous system infection is
Primary herpetic gingivostomatitis is more common in children and primary or results from reactivation. Clinical manifestations include
young adults, with a peak between 6 months and 5 years of age, fever, new onset seizures, and altered mental status.42
and a second peak in the early 20s.32 Herpes simplex viruses have After initial infection, herpes simplex virus remains dormant
been found to enter keratinocytes very quickly, within 5 minutes, at in regional sensory ganglia. Reactivation may be precipitated by
temperatures as low as 7°C by direct membrane fusion.33 The initial triggers such as sunlight, stress, immunosuppression, and trauma.
oral manifestation of herpes simplex virus infection (primary), when Approximately 30% of recurrences are triggered by a precipitating
symptomatic, includes fiery red gingivae and vesicles that will rup- event, such as dental work or minor trauma.31 In some patients, re-
ture into ulcers; systemically, headache, malaise, pharyngitis, fever, activation is heralded by tingling or burning in a 24-­hour prodromal
and cervical lymphadenopathy are notable. Treatment is primar- phase. Clinically, the lesions appear to be tightly clustered vesicles
ily supportive and may include antivirals in some cases (including that can rupture and coalesce, most commonly presenting as herpes
54 | BILODEAU and LALLA

labialis on the vermilion border of the lips and adjacent skin. The it can present on the face or in the mouth along the distribution of
vesicular fluid, if spread to other sites, can lead to autoinoculation. the trigeminal nerve. Intraoral lesions can be seen if the mandibular
When detected in the prodromal phase, recurrent herpes labialis may or maxillary branch of the trigeminal nerve is affected. Treatment
be treated with oral antiviral therapy. A study of 174 patients found includes antivirals, such as acyclovir, to decrease the duration and
a shortened duration of 8.1 days from 12.5 days with treatment with the severity of the lesion, as well as to reduce painful complica-
43
400 mg of acyclovir five times daily for 5 days. A single dose of tions; postherpetic neuralgia can be a significant burden to some
2000 mg of valacyclovir or 1500 mg of famciclovir was also found patients.48,49
44,45
to reduce duration if taken at the onset of prodromal symptoms. Coxsackievirus infection can also lead to vesicular oral ulceration,
Topical zinc oxide and glycerine cream or 1% zinc sulfite gel applied such as herpangina and hand, foot, and mouth disease. Herpangina
every 2 hours during the day have been shown to reduce disease is most commonly seen among young children or young adults. This
duration.46,47 If ointments are applied to lip lesions, care must be manifests as small oral ulcerations that may present on the soft pal-
taken to not allow the ointment to spread onto the perioral skin, ate or tonsillar pillars, accompanied by sore throat and fever. In hand,
leading to lesional spread. Intraorally, in immunocompetent patients, foot, and mouth disease, patients may present with general malaise,
recurrent herpes simplex virus is seen on keratinized bone-­bound sore throat, and fever. Ulcerative lesions may be present at any oral
tissue (attached mucosa) such as the palate and attached gingiva, site (Figure 6A). An erythematous macular rash is usually present on
more commonly on the maxillary gingiva (Figure 5). However, in the hands (Figure 6B) and feet, but it may be present elsewhere on
immunocompromised patients, recurrent infection can be seen on
keratinized and nonkeratinized mucosae.31 Lesions usually heal in A
7-­14 days.
Varicella zoster virus is responsible for chicken pox and herpes
zoster (shingles) infections. The clinical manifestations of chicken
pox (primary infection) may include nonspecific oral ulceration,
itchy rash, fever, malaise, and lymphadenopathy. The virus remains
dormant in dorsal root ganglia until reactivation. Upon reactivation,
prodromal symptoms occur, such as pain, and this is followed by ap-
pearance of vesicular rash. Lesions follow a dermatomal distribution
and manifest as vesicles that eventually rupture. Herpes zoster most
commonly involves the trunk; however, in up to 30% of the cases

F I G U R E 5 Ulcers associated with herpes simplex virus located

on the maxillary palatal mucosa. The ulcers are usually preceded by F I G U R E 6 Ulcers of hand, foot, and mouth disease (A), a palmar
vesicles, and rupturing leads to small crops of ulcers macular rash (B)
BILODEAU and LALLA | 55

the body as well. These lesions are usually self-­limiting and resolve A
within 7-­10 days. However, subsequent infection with other cox-
sackievirus or enterovirus types and strains can result in recurrent
lesions.
Epstein-­Barr virus–related oral ulceration may be seen in patients
receiving immunosuppressive medications such as methotrexate,
azathioprine, cyclosporine, or those with age-­related senescence.
Most lesions occur in the elderly.50,51 Histologically, they are unique
with large “Hodgkin-­
like” Epstein-­ cells.50
Barr virus–positive B-­ B
Clinically, many of the lesions will regress with drug cessation, mak-
ing accurate diagnosis essential.52

7 | M U CO CU TA N EO U S D I S E A S E

A detailed description of the mucocutaneous disorders is beyond

the scope of this chapter, and only a brief description to highlight
the involvement of ulcerative oral lesions is given here. Please
refer to chapters 6 and 8 of this volume for a more comprehensive
discussion.
Lichen planus is a common mucocutaneous condition, usually
involving the oral cavity that affects 1%-­2% of the population. It is
seen most frequently in females in the third to seventh decades of
life. Different clinical forms of lichen planus exist, including reticu-
lar, erythematous, and erosive lichen planus. Reticular lichen planus
may not require treatment, remaining asymptomatic. Clinical oral
manifestations of lichen planus can include oral ulcerations, des-
quamative gingivitis, bleeding gums, altered tasted, and sensitivity
to spicy or acidic foods (Figure 7A). Skin lesions may also be pres-
ent (Figure 7B). In studies of desquamative gingivitis, erosive lichen
planus compromises over 70% of cases.53,54 Biopsy is key for the
diagnosis of suspected ulcerative lichen planus. If a vesiculobullous
disease is in the differential diagnosis, a second specimen should be
submitted for direct immunofluorescence. On hematoxylin-­
eosin
staining, a dense subepithelial lymphocytic band is seen. The epi-
thelium is keratotic with basilar degeneration and the presence of
Civatte bodies (degenerating keratinocytes). A sawtooth appearance
of the rete ridges may be seen. The treatment of oral erosive lichen
planus includes topical steroids (fluocinonide 0.05%, clobetasol
0.05%) or steroid-­
sparing agents including immunosuppressive
agents delivered topically or systemically.55 For patients with des-
quamative gingivitis, a medication tray may be fabricated to deliver
the drug to the affected gingiva.
Erythema multiforme is a mucocutaneous condition that may
be associated with a preceding infection (such as herpes simplex)
or with administration of a systemic medication. Herpes simplex
is especially commonly associated with recurrent cases. Erythema
multiforme is considered to be a type IV delayed-­t ype hypersensi-
tivity reaction, involving a cell-­mediated immune response that re-
sults in destruction of epithelial cells. Oral lesions manifest as large
irregular erosions/ulcers, and hemorrhagic crusting of the lip ver-
million is common. Skin lesions may present as erythematous rings
resembling a bulls-­eye (target lesions). Stevens-­Johnson syndrome
F I G U R E 7 Erosive lichen planus manifesting as desquamative
gingivitis. Areas of ulceration and striae are present on the
maxillary gingiva (A). The skin lesions of a patient with lichen planus
manifest as purple, polygonal, pruritic, papules (B)
is a more severe form, also affecting the eyes or genitals. It is typ-
ically a drug reaction. The most severe manifestation is toxic epi-
dermal necrolysis, involving diffuse sloughing of the skin after drug
exposure.56 Management includes identification and avoidance of
the causative factors and symptomatic management of the lesions.
This includes analgesics for pain and nutritional support. Steroids are
sometimes used for management of erythema multiforme, but their
use is controversial in Stevens-­Johnson syndrome and toxic epider-
mal necrolysis.57 Recurrent cases of herpes simplex–associated er-
ythema multiforme can be prevented by prophylaxis with acyclovir.
Intravenous immunoglobulins have been found to be helpful in man-
agement of toxic epidermal necrolysis.
Benign mucous membrane pemphigoid is a vesiculo-­ulcerative
condition that presents most commonly in middle-­aged adults, with
female predilection. The most common initial presentation is des-
quamative gingivitis and ulcers are uncommon elsewhere, if the gin-
givae are not involved. Whereas oral involvement is most common
(90.2% of cases), ocular (60.1%), nasopharyngeal, laryngeal, genital,
and anogenital mucosae may be involved.58 Patients may report a
history of blistering and, with benign mucous membrane pemphi-
goid, intact bullae may occasionally be seen (Figure 8). Histologically,
subepithelial clefting is seen. It is a type II hypersensitivity reaction
with direct immunofluorescence demonstrating a band at the base-
ment membrane that is positive for immunoglobulin G (IgG), comple-
ment component C3, and/or immunoglobulin A (IgA). Management
56 | BILODEAU and LALLA

disease is characterized by IgG antinuclear antibodies and shaggy

fibrinogen in the basement membrane. Of note, no clear microscopic
features are present to separate chronic ulcerative stomatitis from
lichen planus, so immunofluorescence is required for diagnosis.63
Chloroquine or hydroxychloroquine have been shown to be effec-
tive treatment options.64
Linear IgA disease is a rare mucocutaneous condition that may
present with oral ulcerations or desquamative gingivitis, in addition
to skin lesions.65,66 It is diagnosed by the presence of a distinctive
line of IgA deposited along the basement membrane, detected by
direct immunofluorescence. Treatment involves topical steroids, and
in severe cases systemic steroids and immunosuppressant drugs
may be needed. Case reports have suggested that a combination of
prednisone with either dapsone or sulfapyridine is often effective.67
These latter agents have significant side effects, including hemolytic
F I G U R E 8 An older female with benign mucous membrane
anemia and agranulocytosis, requiring frequent monitoring with
pemphigoid manifests with a large intact bulla on the ventral
blood tests.
tongue

includes the use of topical and/or systemic steroids or steroid-­ 8 | AU TO I M M U N E /S YS TE M I C D I S E A S E S

sparing agents such as the immunomodulators discussed earlier. W ITH A S S O C I ATE D U LC E R ATI O N O F TH E
Pemphigus vulgaris is a relatively rare vesiculo-­
ulcerative O R A L M U COSA
condition that presents most commonly in middle aged to older
adults, with a predilection for the Ashkenazi-­
J ewish popula- Several gastrointestinal diseases have been associated with oral ul-
tion. Intraorally, intact blisters are uncommon. However, jagged, ceration. Celiac disease, also termed gluten-­sensitive enteropathy,
painful chronic ulcers are commonly seen on the hard and soft is precipitated by the ingestion of wheat, rye, or barley in persons
palate, as well as desquamative gingivitis. Dermatologic mani- carrying the DQ2 or DQ8 human leukocyte antigen haplotypes. The
festations, which may or may not be present, include flaccid bul- pathogenesis involves the upregulation of tissue transglutaminase-
lae with erosions that are often preceded by the oral lesions. 59 ­2, which deaminates fragments of gliadin (a component of gluten),
Antibodies are present against Desmoglein-­3 molecules in oral resulting in production of gluten-­specific CD4 cells and subsequent
pemphigus vulgaris lesions and Desmoglein-­1 molecules in muco-
cutaneous lesions. Histologically, suprabasilar clefting is present.
Immunofluorescence demonstrates intercellular deposition of IgG
and, variably, IgA.
Paraneoplastic pemphigus is a rare disorder that affects patients
with certain types of cancers. Multiple vesicular lesions can present
in the oral mucosa. Skin involvement appears polymorphous, man-
ifesting as vesiculobullous lesions or as patches or plaques.60 Eye
involvement may also be present. Management includes the use of
systemic steroids and other immunosuppressive agents.
Epidermolysis bullosa is a group of mucocutaneous disorders,
caused by mutations in genes involved in cell attachment or collagen
production.61 Some of the more severe forms can present with re-
current oral ulceration that heals with scarring. Skin manifestations
are more pronounced, including blistering and scarring. Management
includes palliative care and antibiotics for secondary infection.
Chronic ulcerative stomatitis presents most commonly in fe-
males over the age of 40 and is characterized by recurrent painful
oral ulcers and erosions that have the appearance of lichen planus,
but the lesions may be refractory to treatment with steroids.62 The
pathogenesis is related to autoantibodies against a nuclear protein
called chronic ulcerative stomatitis protein, which appears to be F I G U R E 9 Multiple oral ulcers and fissuring of the soft tissue in
involved in epithelial regeneration. On immunofluorescence, the Crohn's disease
BILODEAU and LALLA | 57

mucosal damage by CD8 T cell activity.68 Oral aphthouslike ulcera-
11
tion may be the first presentation of celiac disease. A comprehen-
sive study that reviewed the literature on oral ulceration in celiac
disease revealed absence of any well-­defined criteria for the diag-
nosis of the oral ulcers as recurrent aphthous stomatitis, whereas
the diagnosis of celiac disease was well supported by biopsy and/
or antibody tests. Although this review concluded that the literature
supports the association between celiac disease and oral ulceration,
ulcers associated with celiac disease should be separately recog-
nized from recurrent aphthous stomatitis.11 Studies reporting that
a proportion of celiac disease–associated oral ulcers respond to a
gluten-­free diet support this conclusion: Oral ulcers that are a mani-
festation of celiac disease respond to a gluten-­free diet, whereas
11
classical recurrent aphthous stomatitis would not.
Both Crohn's disease and ulcerative colitis may manifest in the
mouth as aphthous-like ulcers. The pathogenesis of these inflam-
matory bowel diseases is mediated by a complex interplay between
genetic susceptibility, alterations in the microbiome, and environ-
mental stimuli, resulting in immune dysregulation.69 Also seen in
Crohn's disease are linear ulcers in the vestibule (Figure 9). Arthritis
(26%) and oral ulcers (21%) were the most frequent extraintestinal
manifestations of inflammatory bowel disease in a cohort of 1649
pediatric patients prior to diagnosis.70 Another unique and important
oral manifestation of inflammatory bowel disease is pyostomatitis
vegetans. Clinically, “snail track” pustules comprised of eosinophilic
microabscesses are seen. Treatment of the inflammatory bowel dis-
ease will result in resolution of oral lesions in many cases.
Behcet's disease is a multisystem inflammatory condition that
usually first presents with oral ulceration.71 There is a well-­known
geographic distribution of the disease along the Silk Road route,
with a strong human leucocyte antigen-­B51 association, an antigen
seen in in 2%-­8% of the population in the United States and northern
Europe, but in 20%-­25% of the population in the endemic areas and
in 50%-­90% of patients with Behcet's disease.72 Oral ulcers are pres-
ent in 98.1% of patients with Behcet's disease.73 Subsequently, oc-
ular, genital, gastrointestinal, nervous system, dermal, and vascular
involvement may follow. Diagnostic criteria for Behcet's disease in-
clude recurrent oral ulceration plus any two of the following: recur-
rent genital lesions, eye lesions, skin lesions, or a positive pathergy
test.71 In a series of 258 patients with Behcet's disease followed up

Skin
manifestations Rash? Yes Hand, foot, Algorithm for Evaluation of
present? Yes and mouth disease Recurrent Oral Ulcers Recurrent
Other Skin herpes
lesions? ELP, PV, Linear simplex
Yes virus
IgA, Paraneoplastic
Pemphigus, EM,
SJS Keratinzed
mucosa
Ocular Behcet's,
manifestations? Yes
BMMP, SJ

Yes Minor aphthous

ulcers

Gastrointestinal Yes
manifestations? Crohn's
Location of
lesions

Nonkeratinized
mucosa Major
General Hand-Foot & aphthous ulcer
Yes
manifestations Mouth Disease,
(fever, malaise, Herpangina
Systemic etc.?)
signs or Traumatic
or Yes
symptoms?
chemical
ulceration Chemotherapy
induced BMMP, PV
mucositis or
No Yes medication
induced
ulceration Yes
Both
History of keratinized
Yes and non- Positive
chemical Nikolsky
exposure or keratinized
mucosa sign
clinically
evident source
of irritation? History of
exposure to No
chemotherapeu Erosive Lichen
No tic agents or Individual Planus
ulcer inducing lesions heal Location of
medications? No within 2
lesions
weeks? No

F I G U R E 1 0 An algorithm to assist in the clinical diagnosis of recurrent oral ulcers. BMMP, benign mucous membrane pemphigoid; ELP,
erosive lichen planus; EM, erythema multiforme; IgA, immunoglobulin A; PV, (human) papillomavirus; SJ(S) Stevens-­Johnson (syndrome)
58 | BILODEAU and LALLA
for a mean of 45.8 months, mucocutaneous disease was present in
48.4% of patients, with the most common manifestation being oral
ulceration. Oral ulceration was present more frequently in female
patients (53.6% vs 38.1% of male patients), making this a common
unmet need in Behcet's disease patients with long term follow-­up.74
Thus, oral ulcers can persist even after systemic therapies resolve
the other manifestations of Behcet's disease. A survey of 81 Behcet's
disease patients suggests that psychologic stress and certain foods
may serve as triggers for oral ulceration.75
Systemic lupus erythematous is a complex autoimmune
disease comprised of multiple subtypes with over 30 single-­
nucleotide polymorphisms implicated in the pathogenesis, and
76
influencing the clinical manifestations. Ninety percent of pa-
tients with systemic lupus erythematous are female with a three
to four times increase in incidence in African American patients.77
Oral lesions are present in approximately 21% of patients with
systemic lupus erythematous and are associated with increased
78,79
disease activity and a worse prognosis. The pathogenesis
of systemic lupus erythematous involves dysregulation of cel-
lular, humoral, and innate immunity, with findings supportive of
an overly active mucosal immune system with increases in IgA
plasmablasts. 80 Genotyping of 4001 patients for 16 loci associ-
ated with systemic lupus erythematous found an association with
STAT4 and protection of systemic lupus erythematous patients
from oral ulceration.77 Genotyping of 482 patients has impli-
cated vascular endothelial growth factor in oral ulceration in the
context of systemic lupus erythematous, suggesting a potential
for targeted therapies. 81 The lesions include areas of ulceration
and lichenoid-­t ype lesions. The lichenoid areas will demonstrate
a mixed inflammatory infiltrate, with a variable density, usually
extending relatively deeply into the connective tissue and may
extend perivascularly. Basement membrane thickening may be
present, which can be confirmed with periodic acid-Schiff stain-
ing. However, the diagnosis of lupus erythematous should be con-
firmed with testing for antinuclear antibodies. Topical steroids are
useful in treating the oral lesions.
Less common conditions that may be associated with recurrent
oral ulceration include Reiter's syndrome, MAGIC (mouth and gen-
ital ulcers with inflamed cartilage) syndrome, Sweet's syndrome,
and cyclic neutropenia. MAGIC syndrome consists of a constella-
tion of clinical findings, including chondritis, oral aphthous ulcers,
ocular inflammation, and genital ulcers. Clinically, significant over-
lap with the lesions of Behcet's disease is seen, but polychondritis
is a unique facet. 82 Sweet's syndrome (acute febrile neutrophilic
dermatosis) presents most commonly in middle-­aged females and
is characterized by fever, malaise, leukocytosis, tender erythem-
atous skin nodules, and recurrent oral ulcerations. Up to 20% of
patients with Sweet's syndrome have an underlying malignancy,
most commonly acute myelogenous leukemia. 83 Cyclic neutrope-
nia is an autosomal dominantly inherited disorder that presents in
childhood characterized by cycles of neutropenia of ~21 days. In
the 3-­to 4-­day neutropenic phase there may be fever, malaise, aph-
thous ulceration, arthralgia, bacterial infections, and various other
symptoms. Diagnosis is established by serial blood work to doc-
ument periodic neutropenia. 84 There is some controversy in the
literature as to whether periodic fever, aphthous stomatitis, phar-
yngitis, and adenitis is a distinct entity, but it is another described
entity associated with recurrent aphthous ulcers.11 This condition
presents in the pediatric population with systemic malaise, aph-
thous stomatitis, fever, and tonsillitis (with cultures negative for
beta hemolytic streptococci) and is a diagnosis of exclusion. The
management of the oral ulcers in this condition is based on the se-
verity of the lesions. Glucocorticoids, tonsillectomy, and cimetidine
are the treatments described for this entity. Spontaneous remis-
sion can occur. 84 Topical steroids and “magic mouthwash” are the
mainstays of treatment of the oral lesions. 85 (Magic mouthwash is a
term used for some over-­the-­counter products and some which are
specifically compounded. They contain various mixtures of an an-
tibiotic, an antihistamine, an antifungal, a corticosteroid, and often
an antacid.)
9 | A LG O R ITH M FO R E VA LUATI O N O F
R ECU R R E NT O R A L U LC E R S
Many important considerations exist when clinically evaluating oral
ulcers. The number of ulcers, duration, location, and clinical appear-
ance (size and depth) should be noted. A thorough history should
be taken, seeking any systemic symptoms that may exist or the
presence of ulcers elsewhere in the body. A suggested diagnostic
algorithm, covering the more common causes of recurrent oral ul-
ceration, is presented in Figure 10.
10 | CO N C LU S I O N S A N D FU T U R E
D I R EC TI O N S
As described in this chapter, recurrent oral ulcerations can result
from a variety of disparate etiologies and, therefore, may pose a
diagnostic challenge. Historically, the diagnosis of many of these
conditions has been made based only on clinical presentation,
sometimes along with tissue biopsy. However, not every case will
present the typical clinical or histological features associated with
a certain condition. The management of many of these conditions
has been similarly nonspecific, often involving nontargeted anti-­
inflammatory or immunosuppressive agents. There is a clear need
for further studies of the molecular etiopathogenesis of these
conditions that should allow for the identification of more-­specific
molecular targets for development of diagnostic tests and for
therapeutic intervention.
AC K N OW L E D G M E N T S
We thank Dr Kurt Summersgill, University of Pittsburgh School of
Dental Medicine, Department of Diagnostic Sciences, for his contri-
bution of clinical images and manuscript review.
BILODEAU and LALLA
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How to cite this article: Bilodeau EA, Lalla RV. Recurrent oral
ulceration: Etiology, classification, management, and diagnostic
algorithm. Periodontol 2000. 2019;80:49–60. https://doi.
org/10.1111/prd.12262