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Volume 46 Number 1 March 2013

Unidentified angular recurrent ulceration responsive to antiviral 
therapy

rahmi amtha1 and Siti aliyah Pradono2
1Department of Oral Medicine, Faculty of Dentistry, Universitas Trisakti
2Department of Oral Medicine, Faculty of Dentistry, Universitas Indonesia
Jakarta - Indonesia

abstract

Background: Recurrent ulcer on angular area is usually called stomatitis angularis. It is caused by many factors such as vertical 
dimension reduce, vitamin B12, and immune system deficiency, C. albicans and staphylococcus involvement. Clinically is characterized 
by painful fissure with erythematous base without fever. Purpose: to describe an unidentified angular ulcer proceeded by recurrent 
ulcers with no response of topical therapy. Case: An 18-years old male came to Oral Medicine clinic in RSCM who complained of 
angular recurrent ulcers since 3 years ago which developed on skin and bleed easily on mouth opening. Patient had fever before the 
onset of ulcers. Large, painful, irregular ulcers covered by red crustae on angular area bilaterally. Patient has been treated with 
various drugs without improvement and lead to mouth opening limitation. Intra oral shows herpetiformtype of ulcer and swollen of 
gingival. Case management: Provisional diagnosis was established as viral infection thus acyclovir 200 mg five times daily for two 
weeks and topical anti inflammation gel were administered. Blood test for IgG/IgM of HSV1 and HSV2 were non reactive, however 
ulceration showed a remarkable improvement. The ulcers healed completely after next 2 weeks with acyclovir. Conclusion: The 
angular ulceration on above patient failed to fulfill the criteria of stomatitis angularis or herpes labialis lesion. However it showed a 
good response to antiviral. Therefore, unidentified angular ulceration was appointed, as the lesion might be triggered by other type 
of human herpes virus or types of virus that response to acyclovir. 

Key words: Unidentified angular ulceration, anti inflammatory gel, acyclovir

abstrak

latar belakang: ulser rekuren pada sudut mulut biasanya disebut stomatitis angularis. Kelainan ini disebabkan oleh banyak faktor 
seperti berkurangnya dimensi vertikal, defisiensi vitamin B12 dan sistem kekebalan tubuh, infeksi C. albicans serta staphylococcus. Secara 
klinis kelainan ini ditandai dengan fisur sakit pada sudut mulut dengan dasar eritematus tanpa disertai demam. tujuan: Melaporkan 
kasus ulser sudut mulut rekuren yang tidak biasa, tanpa respon terhadap terapi topikal yang biasa diberikan. Kasus: Seorang laki-
laki berusia 18 tahun datang ke klinik Penyakit Mulut RSCM dengan keluhan ulser rekuren pada sudut mulut yang meluas ke kulit 
sekitarnya sejak 3 tahun yang lalu. Ulser mudah berdarah saat pasien membuka mulut dan demam sebelum lesi timbul. Ulser membesar, 
bilateral, sakit, tepi tidak teratur, ditutupi oleh krusta merah. Pasien telah diobati dengan berbagai obat, namun tidak menunjukkan 
perbaikan. Intra oral tampak ulser jenis herpetiformis pada gingiva disertai dengan pembengkakan. tatalaksana kasus: Diagnosis 
awal ditegakkan sebagai infeksi virus, oleh karena itu pasien diberikan acyclovir 200 mg lima kali sehari selama dua minggu dan gel 
anti radang topikal. Walaupun hasil darah IgG/IgM HSV1 dan HSV2 non reaktif, namun ulserasi menunjukkan penyembuhan yang 
luar biasa dengan anti virus yang diberikan. Ulser sembuh sempurna setelah pemakaian acyclovir 2 minggu berikutnya. Kesimpulan: 
ulserasi sudut mulut pada pasien di atas gagal memenuhi kriteria stomatitis angularis atau herpes labialis. Namun ulser menunjukkan 
respon yang amat baik terhadap antivirus. Diagnosis ditetapkan sebagai ulserasi sudut mulut yang tidak teridentifikasi. Kemungkinan 
lesi dipicu oleh virus herpes manusia jenis lain atau jenis virus yang memberikan respon terhadap asiklovir. 

Kata kunci: Ulser sudut mulut tidak teridentifikasi, gel anti radang, asiklovir

Correspondence: Rahmi Amtha, c/o: Departemen Penyakit Mulut, Fakultas Kedokteran Gigi Universitas Trisakti. Jl. Kyai Tapa Grogol, 
Jakarta 11440, Indonesia. E-mail: rahmi.amtha@gmail.com

Case Report



��Amtha and Pradono: Unidentified angular recurrent ulceration responsive to antiviral therapy

introduction

In daily practice, it is common to find an angular 
ulceration which can be triggered by many factors. 
Cheilitis is a broad term description of inflammation of 
the lip surface characterized by dry scaling and fissuring. 
There are some types of cheilitis such as atopic, angular, 
granulomatous, and actinic. Angular cheilitis is commonly 
seen and it specifically refers to cheilitis that radiates 
from the commissures or corners of the mouth. Other 
terms synonymous with angular cheilitis are perlèche, 
commissural cheilitis or angular stomatitis.1 Clinically 
angular cheilitis appears as redness, ulceration and fissuring 
either unilateral or bilaterally at the corners of the mouth. 
It can appear alone or in conjuction with another form of 
candidiasis. Cheilitis angularis is a syndrome that involves 
several factors. The factors may play role individually 
or interchangeably. Candida albicans, Staphilococus 
aureus, vertical dimension decreasing, vit B12 deficiency 
until immune deficiency (such as in HIV patients) are the 
established predisposing factors of angular cheilitis.2,3 

However, occasionally the clinical manifestation shows 
unpathognomonic or unspecific clinical appearance with 
recurrent episodes and involves general conditions. This 
condition may make the provisional diagnosis sometimes 
difficult to be established and need further analysis to be 
able to treat the ulcers. 

Ulceration at the corner of the mouth can be also as 
the manifestation of secondary herpes simplex infection. 
Typically, lesions are located on the vermillion border of 
the lips (herpes labialis, “cold sores or “fever blister), but 
may develop elsewhere in the mouth, on the face or inside 
the nose. The initial primary episode of herpes labialis 
occurs 1 to 26 days after inoculation and can appear as 
multiple blisters, 1–2 mm in size, associated with severe 
discomfort that lasts for 10 to 14 days.4 Recurrent herpes 
labialis may affect about one-third of the population in the 
world, with episodes usually occurring from one to six times 
per year.4 Orolabial recurrent herpesvirus infections can be 
triggered by stimuli such as fever, stress, cold, menstruation 
and ultraviolet radiation. Prodormal symptoms, including 
paraesthesia, tenderness, pain, burning sensation, tingling 
or itching sensation at the site of viral re-activation, arise 
in 46–60% of patients, and last for about 6 hours.5 

Some autoimmune diseases such as erythema 
multiforme eruption is known to have an association 
with those who have history of recurrent herpes simplex 
infection. Erythema multiforme ranges from mild, severe 
to potentially life-threatening, and can involve acutely 
painful oral and labial ulcers.6 Herpes simplex virus or 
other viral infections may precipitate erythema multiforme 
in the oral cavity.6-8 Besides herpes simplex virus, there are 
some other human herpes viruses that may induce the oral 
ulcerations. Eight human herpesvirus species with distinct 
biological and clinical characteristics have been described: 
herpes simplex virus-1, herpes simplex virus-2, varicella–

zoster virus, Epstein–Barr virus, human cytomegalovirus, 
human herpesvirus-6, human herpesvirus-7 and human 
herpesvirus-8. Each herpesvirus subfamily maintains latent 
infection in specific cell population(s). Alpha herpesviruses 
exhibit a relatively short reproductive cycle, rapid lyses of 
infected cells and latency in sensory ganglia.9 

Herpes simplex virus and cytomegalovirus are also 
reported to be potential pathogens of Behcet’s syndrome 
ulcerations and Pemphigus vulgaris (an intraepidermal 
bullous disease which frequently involves large recalcitrant 
oral ulcers that precede the onset of skin lesions). Further 
research is needed to determine the extent to which viruses 
are involved in the oral ulcerogenesis of these and other 
systemic diseases, including Crohn’s disease, ulcerative 
colitis and neutropenia.9 

Epstein–Barr virus is involved in a great variety 
of cancers. The virus possesses factors capable of 
immortalizing B lymphocytes and epithelial cells, contains 
several potentially oncogenic antigens Epstein–Barr virus is 
associated with numerous lymphoid proliferations, including 
African Burkitt's lymphoma, classical Hodgkin’s disease 
and recurrent periodontal disease.10 The Epstein–Barr virus 
is present in two-thirds of AIDS-related lymphomas.11 In 
the oral cavity, Epstein–Barr virus has been identified in 
Hodgkin’s lymphoma, Burkitt’s lymphoma, cyclosporine-
related post-transplant lymphoproliferative disorder, post-
transplant diffuse B-cell lymphoma, follicular lymphoid 
hyperplasia and plasmablastic lymphoma. Demographic, 
geographic and environmental factors may be important, 
as most studies showing a herpes viral association with 
oral tumors originate from Asian countries. Epstein–Barr 
virus-related nasopharyngeal carcinoma is known to occur 
with a high relative prevalence in natives of southern China 
and southeast Asia,12 which may be a result of ethnically 
determined host–virus interactions or distinct Epstein–Barr 
genotypes predominating in some Asian populations. 

Human cytomegalovirus genome and antigens have 
been identified in malignant tumors, including colon cancer, 
malignant glioblastoma. Cytomegalovirus is a member of the 
herpes family of DNA viruses. Herpes viruses are capable of 
latency after infection with an acute disease followed by an 
asymptomatic, quiescent state. Fifty to ninety five percent 
of adults have antibodies against CMV.13 Infection with 
CMV in most immunocompetent hosts is asymptomatic 
but can present as a mononucleosis-like syndrome.14,15 
Cytomegalovirus is the virus most frequently isolated 
from people with AIDS. Ninety percent of patients with 
AIDS are infected with CMV, and disseminated CMV is 
found during autopsy in 93% of patients with AIDS. There 
are infrequent reports in the literature of cutaneous CMV 
infections. This may be because cutaneous CMV infections 
are uncommon or because making a diagnosis of CMV is 
difficult as a result of its multiple clinical presentations and 
subtle histopathological findings. Below is the case report 
of patient who have an recurrent angular ulceration which 
show a good improvement with antiviral agent. 



�� Dent. J. (Maj. Ked. Gigi), Volume 46 Number 1 March 2013: 30–34

case 

An eighteen years old man came to Oral Medicine clinic 
in Cipto Mangunkusumo Hospital to seek for treatment of 
recurrent angular ulcer since four days ago that developed to 
skin and bleed easily on mouth opening. Patient had slight 
fever before the onset of ulcers. Large, painful, irregular 
ulcer covered by red crustae found on bilateral angular area 
(Figure 1). Ulcers appear at least twice a year for last three 
years and always preceded by slight fever and herpetiformis 
type of ulcer on the commissure, upper and lower lip 
bilaterally, floor of the mouth and absence of skin ulcers. 
Upper and lower gingival showed pseudomembranous and 
slightly inflamed on interdental papilla (Figure 2). Ulcers 
healed ranging in 2-3 weeks. Patient has seen medical 
doctors and been given antibiotic, analgesic, some topical 
agent (triamcinolone acetonide ointment, albotyl®, Chinese 
green traditional powder) and variety of mouthwashes. 
However, the ulcer showed no improvement and lead to a 
deeper and wider ulcer develop to surrounding skin, easy 
to bleed and cause limitation of mouth opening. Patient 
stays in dormitory with sufficient facilities and admits no 
psychological stress. Patient’s diet pattern shows normal 
and likes to eat vegetables and drink a lot of water. Patient 
is non smoking and non alcohol drinking and use sodium 
lauryl sulfate dental paste. On the first day of visit, patient 
looked depressed due to unhealed ulcers and showed 
reluctant in replying question during anamnesis because of 
painful and bleeding ulcers. Hematological results (ordered 
by previous doctors) showed an increase in erythrocyte 
sedimentation rate (ESR), erythrocyte and hemoglobin and 
negative of Widal test.  

Based on the history of slight fever and the herpetiform 
type of ulcer preceded the bilateral angular ulcer, two 
provisional diagnosis were established as herpes labialis 
or ertythema multiforme triggered by herpes simplex 
infection (HAEM). Thus, acyclovirs 200 mg five times 
daily, hyaluronic acid gel and multivitamin once a day for 
two weeks were administered on the first visit. Blood test 
for IgG/IgM of HSV1 and HSV2 was ordered. 

Second visit (10 days later): After ten days patient 
came again for first control. The angular ulcers as well 
as the surrounding skin showed remarkable improvement 
(Figure 3). There was no red crustae seen over the lesion. 
Thin fissure with yellowish base and desquamation still 
obvious on the angular area without bleeding tendency 
every time patient opened his mouth. No other ulcers 
found on the upper, lower lips and floor of the mouth. The 
laboratory result showed IgG and IgM for HSV 1 and HSV 
2 were no reactive/normal. Acyclovir 200 mg 5 times a day 
for 2 weeks and multivitamin once daily were continued. 
Fucidin ointment was administered three times a day to 
help recovery of the skin and prevent further involvement 
of bacteria (staphylococcus). 

Third visit (15 days later): On the second control, patient 
looked satisfy that the angular ulcer has completely healed 
without skin desquamation, scar and soreness. The recovery 

tissue still looked pale compared to surrounding tissue; 
however follicle and sebaceous gland near commissural 
area showed well emerge (Figure 4). Therefore, patients 
was discharged with instruction to maintain the oral hygiene 
and have enough rest. The update interview is done by 
phone one month before this case is reported, showed that 
patient has no longer oral ulcers including at the angular 
area as before. 

discussion

By looking to the clinical manifestation, the angular 
ulcers in this case cannot be called as a classic cheilitis 
angularis as the manifestation expressed differently from 

figure 1.  Bilateral chronic multiple angular ulcer covered with 
red crustae which easy to bleed (1st visit).

figure 2.  Slight edematous on upper and lower gingival, coexist 
with multiple minor ulcer on lower lip (1st visit).

figure 3.  Angular ulcers showed remarkable healing with still 
desquamation (2nd visit) the 10th days.

 

figure 4.  Complete healing of the angular ulcers bilaterally (3rd 
visit) the 15th days.



��Amtha and Pradono: Unidentified angular recurrent ulceration responsive to antiviral therapy

the common cheilitis angularis which caused by nutritional 
deficiencies, reduction of vertical dimension, microorganism 
involvement or allergy. Moreover, the background of 
recurrent onset with slight fever and do not response to 
any topical agent (anti ulcer) lead to possibility of recurrent 
ulcers due infection of human herpes virus, usually herpes 
simplex (HSV). The severe clinical appearance on the first 
visit, which showed angular ulcers with tendency of bleed 
easily coincide with multiple herpetiform ulcers in the 
mouth is also leading to further autoimmune disease which 
associated with herpes virus infection. HSV infection is a 
predominant preceding event in individuals that experience 
recurrent episodes of Erythema Multifome (EM), and 
such individuals are labeled as having herpes-associated 
erythema multifome (HAEM). However, usually the EM 
skin lesions characteristically occur 1 to 10 days after 
an episode of herpes labialis or genitalis, which did not 
appear in this case. It was strengthened by the laboratory 
results of HSV1 and HSV2 IgG/IgM that showed normal 
(non reactive). Weston16 has reported that seven of 34 
patients with HSV had detectable HSV DNA in peripheral 
blood mononuclear cells (PBMC) isolated, these subjects, 
however, did not develop EM. This led some researchers to 
believe that HSV is transported to skin lesions via the blood, 
but further noted that HSV-specific antibody responses 
and lymphocyte transformation responses to HSV antigens 
were similar in-group with or without HSV infection. 
Therefore, they found that HAEM occurred in spite of 
high immunity. Aurelian in year 2005 also reported that 
subjects with HAEM have detectable herpes simplex viral 
particles in their circulating peripheral blood CD34 cells 
and it presumably destined to be precursors of epidermal 
Langerhans cells.17 The findings found that patients with 
recurrent herpes labialis or genitals but without episodes of 
EM did not have detectable virus in this type of cells.16 

The administration of anti viral for the second visit 
was still prescribed eventhough the laboratory results 
of IgG/IgM of HSV showed negative. The reason was 
because the ulcers showed a significant improvement 
with the antiviral given. This is supported the findings by 
Weston16 and Aurelian17 regarding the non-specific antigen 
of HSV found in case of erythema multiforme. Therefore 
the positive response of the ulcers with anti viral agent is 
in consequence of possibility of triggered by one or more 
type of human herpes virus (HHV). As we know that 
HHV has 8 types and their oral manifestation has not been 
completely elaborated and studied. So that when IgM/IgG 
of HSV were tested showed negative. It is assumed that 
this type of virus did not induce the ulcers and it needs 
further study. Furthermore, It is probable that several of 
the risk factors for oral ulceration cause lesion outbreak by 
activating a latent viral infection that is not herpes simplex 
type of virus. Also, some viruses may induce oral ulceration 
when co-infecting with other viruses. In this case, stress, 
nutritional deficiency and lack of rest can be the risk factors, 
even though there was not a specific test done to describe 

that condition and patient did not admit that he was under 
pressure in his dorm life of style. 

Widespread and multiple oral ulcers should raise the 
suspicion of skin disease or vasculitis, particularly if 
associated with mucocutaneous lesions (e.g. blistering, 
hyperkeratosis or scarring); and ulcers limited to the 
commissures (angular cheilitis) have typically a microbial 
basis (often a candida or staphylococcal infection). 

History of recurrent angular ulcers and herpetiform 
ulcerations with fever is the basic of decision of prescribing 
the anti viral in this patient, besides increasing immune 
system by instruction of enough rest and multivitamin. The 
response of using corticosteroid (triamcinolone ointment) 
showed no improvement of the lesions and actually a 
contraindication for viral infection except for bell’s palsy 
type of case with background of HSV reactivation. There is 
no harmful side effect of giving patient of standard dosage 
of anti viral as the empirical treatment. As mentioned 
in previous research that one of eight people showed 
detectable particle of human herpes virus in their peripheral 
blood cells but not as the complete genome of the viral, so 
that the IgG/IgM found no reactive.16,17 Moreover, all the 
human herpes virus has showed positive response to anti 
viral acyclovir. 

The fucidin ointment is an optional treatment to 
eliminate the involvement of staphylococcus infection on 
the skin surrounding ulcers. Some clinical trial also showed 
that it helps to regenerate the skin texture damage. In this 
case, recurrent angular ulcers showed severe ulcers until 
involve deeper surrounding dermis. 

Finally, as clinicians sometime it is difficult to 
determine one fixed diagnosis as the clinical appearance 
of oral ulcers is often not pathognomonic, and several 
different ulcerogenic conditions of the mouth may currently 
be lumped together. The best approach can be done is to 
review the basic pathogenesis of the disease to establish 
the best treatment. 

Angular cheilitis terminology has a broad meaning and 
approach of treatment. The variety of clinical appearance 
and history of onset may lead to some diagnosis which is 
caused by viral infection. The angular ulceration on above 
patient failed to fulfill the criteria of stomatitis angularis or 
herpes labialis lesion. However it showed a good response 
to antiviral. Therefore, unidentified angular ulceration was 
appointed; as the lesion might be triggered by other type 
of human herpes virus or types of virus that response to 
acyclovir. 

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