Erythema multiforme case report

YU-FENG HUANG1 HUI-WEN YANG2 JEN-HONG YANG3

1

Oral Medicine Center, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.
Department of Dentistry, College of Oral Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
3
Department of Dermatology, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.
2

Erythema multiforme (EM) is an acute mucocutaneous disease which has been associated with
herpes simplex virus (HSV) infection, drugs, and Chinese herbal medicine. This report presents a case
of EM with a delayed diagnosis and improper treatment. A 28-year-old female patient came to our oral
medicine clinic with a chief complaint of multiple oral ulcerations for more than 3 months. She was
treated as having an HSV infection or candidiasis, but the oral lesions did not improve after treatment.
An intraoral examination showed multiple large ulcers on the bilateral lateral borders and ventral surface
of the tongue, bilateral buccal mucosae, and lingual frenum. No target lesion was found on the skin
surface of her body or extremities. An incisional biopsy of the tongue tip was performed. The
hematoxylin and eosin-stained tissue section demonstrated focal surface ulceration, an intraepithelial
vesicle in the upper spinous layer, an intense chronic inflammatory cell infiltrate in the lamina propria,
and a perivascular inflammatory infiltrate in the submucosa. Although the histopathologic features were
not pathognomonic, they were characteristic for a diagnosis of EM. The patient was treated with 10 mg
prednisolone 3 times daily for 7 days. A follow-up oral examination revealed that all oral ulcers had
completely cleared up after the 7-day corticosteroid treatment. One year after treatment, the patient
remained disease-free. We concluded that EM is a mucocutaneous disease that requires a prompt and
precise diagnosis. Once the disease is confirmed by the clinical presentation or a histopathological
examination of an incisional biopsy specimen, it usually dramatically responds to treatment with a
medium or high dose of corticosteroids. J Dent Sci, 1(2)94-97, 2006
Key words: erythema multiforme, corticosteroids.

Erythema multiforme (EM) is an acute

mucocutaneous disorder that is believed to be a
sequela of a cytotoxic immunologic attack on
keratinocytes expressing non-self-antigens, which are
primarily caused by microbes (viruses)1-3, drugs4, or
Chinese herbal medicine5.
The severity of the
disorder varies from a self-limited, mild, exanthematous, cutaneous variant with minimal oral
involvement (EM minor) to a progressive, fulminating, severe variant with extensive mucocutaneous
epithelial necrosis (Stevens-Johnson syndrome and

Received: March 24, 2006

Accepted: May 30, 2006
Reprint requests to:Dr. Yu-Feng Huang, Department of Dentistry, Oral
Medicine Center, Chung Shan Medical University
Hospital, No. 110 Chien-Kuo N. Road, Sec. 1,
Taichung, Taiwan 402, ROC.

94

toxic epidermal necrolysis). EM usually affects

apparently healthy young adults, and several reports
have suggested that males are affected more
frequently than females. The peak age of occurrence
of EM is between 20 and 40 years, although 20%
of cases occur in children. The disease is often
recurrent and is precipitated by a preceding herpes
simplex virus (HSV) infection in up to 70% of cases6.
Clinically, EM minor is considered to be the
mildest form of EM and is characterized by classic
skin lesions that are called iris or target lesions on
the extremities. The lesions may be itchy and
accompanied by systemic symptoms such as fever
and malaise1. By definition, mucous membrane
involvement is limited to only 1 site, and usually only
the oral mucosa is affected7. Moreover, the lesions
may occur primarily in the oral cavity prior to their
appearance on the skin. Intraoral lesions pre-

J Dent Sci 2006Vol 1No 2

Erythema multiforme

dominantly occur on the non-keratinized mucosae and

are most pronounced in the anterior part of the mouth,
including the lips and tongue6. Intraoral lesions
present as widespread macules to blisters that coalesce
to form large ulcerations. A diagnosis of EM is often
based on the clinical presentation, although an
incisional biopsy of the perilesional tissue may be
helpful. Although the microscopic features of EM
are not pathognomonic, they show intraepithelial
edema and spongiosis with individual eosinophilic
necrotic keratinocytes, vacuolar degeneration of the
junctional zone, severe papillary edema with sub- or
intraepithelial vesiculation, and an intense lymphocytic infiltrate in the subepithelial connective
tissue with occasional perivascular cuffing.
The purpose of this case report is to present an
uncommonly seen case of EM which was improperly
diagnosed and treated, as well as to discuss the
differential diagnosis of this ulcerative disease.

Clinical photograph showing a large ulceration with

a ring of an erythematous border on the left buccal mucosa near
the mouth angle.

Figure 1.

CASE PRESENTATION
This 28-year-old female patient came to our oral
medicine clinic at Chung Shan Medical University
Hospital with a chief complaint of multiple oral
ulcerations for more than 3 months. She had visited
several dental or medical clinics and was treated for
an HSV infection or candidiasis, but the oral lesions
did not improve after treatment.
In general, she was healthy and was not taking
any medications, except those prescribed for the HSV
infection and candidiasis. She had never had such an
episode before and was afebrile.
An intraoral
examination showed multiple large ulcers on the
bilateral lateral borders and ventral surface of the
tongue, the bilateral buccal mucosae, and lingual
frenum. The ulcer on the buccal mucosa was
irregular in shape with a well-demarcated ring as an
erythematous border (Figure 1). The surface was not
covered by a necrotic pseudomembrane. These ulcers
were very painful and prevented her from carrying out
her daily routines. No target lesion was found on the
skin surface of her body or extremities.
An incisional biopsy of the tongue tip was
performed. The hematoxylin and eosin-stained tissue
section demonstrated a focal surface ulceration at the
edge of the specimen. The adjacent epithelium was
hyperplastic and hyperkeratotic with an intraepithelial
vesicle in the upper spinous layer. An intense

J Dent Sci 2006Vol 1No 2

Figure 2. Biopsy of the lesion at the tongue tip revealing a focal

surface ulceration (white arrow), an intraepithelial vesicle (black
arrow) in the upper spinous layer, an intense chronic inflammatory
cell infiltrate in the lamina propria (black arrowheads), and a
perivascular inflammatory infiltrate in the submucosa (white
arrowhead).

chronic inflammatory cell infiltrate was found in

the lamina propria. In addition, a perivascular
inflammatory infiltrate was also noted in the
submucosa (Figure 2). Because no characteristic
features like acantholysis or separation of the
epithelium from the lamina propria were found,
vesiculobullous diseases such as pemphigus vulgaris
95

Y. F. Huang, H.W. Yang, J. H. Yang.

Clinical photograph demonstrating how the oral

ulcerations had healed after the 1-week corticosteroid treatment.

Figure 3.

and cicatricial pemphigoid could respectively be ruled

out. Although the histopathologic features were not
pathognomonic, they were characteristic of a
diagnosis of EM. No immunofluorescent or immunohistochemical analyses were performed because
these special procedures were unlikely to have yielded
any useful information for the final histopathological
diagnosis of EM.
The patient was treated with 10 mg of prednisolone 3 times daily for 7 days. A follow-up oral
examination revealed that all oral ulcers had
completely cleared up after the 7-day corticosteroid
treatment (Figure 3). One year after treatment, the
patient remained disease-free.

DISCUSSION
The differential diagnosis of multiple oral
ulcerations like those presented in this case may
include pemphigus vulgaris, cicatricial pemphigoid,
oral aphthous ulcerations, HSV infection, and EM.
Pemphigus is a mucocutaneous disease with an
autoimmune etiology. Although various types of
pemphigus are present, only pemphigus vulgaris is
likely to involve the oral mucosa.
Clinically,
pemphigus vulgaris can involve all oral mucosae
showing superficial vesicles that rupture easily and
become ulcers.
Histopathologically, the disease
shows acantholysis which results in a suprabasal split
96

in the epithelium. An immunofluorescence study

can demonstrate a deposition of autoantibodies in the
intercellular areas between the epithelial cells. The
biopsy specimen in this case showed no acantholysis
or the characteristic suprabasal split, thus a diagnosis
of pemphigus vulgaris could be ruled out.
Cicatricial pemphigoid, or benign mucous
membrane pemphigoid, is also a mucocutaneous
disease with an autoimmune etiology. The disease
may involve both the oral mucosa and the conjunctiva,
which if not properly treated, may lead to blindness.
Clinically, the gingiva is the most common location
for cicatricial pemphigoid. Histopathologically, a
clear separation of the epithelium from the underlying
lamina propria can be discerned by light microscopy,
and an immunofluorescence study can demonstrate
linear positivity along the basement membrane. The
biopsy specimen in this case showed no clear
epithelium-connective tissue separation, thus a
diagnosis of cicatricial pemphigoid could be ruled out.
It would be clinically challenging to distinguish
oral aphthous ulcerations from EM, if the lesions of
EM were only present in the mouth. Minor aphthous
ulcerations usually show painful round ulcers smaller
than 1 cm in diameter on the non-keratinized mucosa.
The ulcers are often covered by a necrotic pesudomembrane and heal in 7~14 days. However,
major aphthous ulcerations may demonstrate single or
multiple painful ulcers larger than 1 cm in diameter
that last for more than 1 month before healing occurs.
In this case, the histopathological features showed an
intraepithelial vesicle and a perivascular inflammatory
infiltrate, which are characteristic of EM and are
relatively rarely seen in aphthous ulcerations8.
The differential diagnosis in this case included
HSV infection, both primary and secondary. Our
patient denied any similar previous episode, and no
systemic signs or symptoms such as cervical
lymphadenopathy, chills, fever, fatigue, and malaise
which are characteristic of primary HSV infection
were present in this case. In secondary herpetic
gingivostomatitis, multiple small vesicles are usually
found in a cluster on the gingiva and hard palate. Our
patient had multiple large ulcers on the bilateral lateral
borders and ventral surface of the tongue, bilateral
buccal mucosae, and lingual frenum. Microscopically,
oral herpetic lesions may show intraepithelial vesicles,
but there are usually altered epithelial cells exhibiting
ballooning degeneration, chromatin margination, and
multinucleation in the vesicular fluid. Because these
J Dent Sci 2006Vol 1No 2

Erythema multiforme

altered epithelial cells were not seen in this case, HSV

infection could be ruled out.
Although the use of corticosteroids for treating
EM is controversial6, it remains the main treatment
modality for EM minor8, such as in this case. The
patient was treated with a medium dose of corticosteroids for 1 week, and the oral ulcerations healed
without subsequent recurrence for 1 year. The
patients dramatic response to steroid treatment and
the absence of recurrence for 1 year also favor a
diagnosis of EM, and help rule out the possibility of
pemphigus vulgaris, cicatricial pemphigoid, and oral
aphthous ulcerations which are either refractory to
treatment or more recurrent in nature. In addition,
steroid treatment is contraindicated for HSV infection;
if the patients disease had been an HSV infection, she
would not have experienced the dramatic response to
the steroid treatment.
In conclusion, EM is a mucocutaneous disease
that requires a prompt and precise diagnosis. Once the
disease is confirmed by the clinical presentation or a
histopathological examination of an incisional biopsy
specimen, it usually dramatically responds to
treatment with a medium or high dose of corticosteroids.

J Dent Sci 2006Vol 1No 2

REFERENCES
1. Ayangco L, Rogers RS, III. Oral manifestations of erythema
multiforme. Dermatol Clin, 21: 195-205, 2003.
2. Ng PP, Sun YJ, Tan HH, Tan SH. Detection of herpes simplex
virus genomic DNA in various subsets of Erythema
multiforme by polymerase chain reaction. Dermatology, 207:
349-353, 2003.
3. Aurelian L, Ono F, Burnett J. Herpes simplex virus
(HSV)-associated erythema multiforme (HAEM): A viral
disease with an autoimmune component. Dermatol Online J,
9: 1-7, 2003.
4. Ahmed I, Reichenberg J, Lucas A, Shehan JM. Erythema
multiforme associated with phenytoin and cranial radiation
therapy: a report of three patients and review of the literature.
Int J Dermatol, 43: 67-73, 2004.
5. Tan WP, Goh BK, Tan SH. Extensive erythema multiforme-like eruption due to traditional Chinese herbal drug
'Dong Ling Hou Tong Pian'. Clin Exp Dermatol, 31: 291-293,
2006.
6. Farthing P, Bagan JV, Scully C. Mucosal disease series.
Number IV. Erythema multiforme. Oral Dis, 11: 261-267,
2005.
7. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a
critical review of characteristics, diagnostic criteria, and
causes. J Am Acad Dermatol, 8: 763-775, 1983.
8. Neville BW, Damm DD, Allen CM, Bouquot JE. In Oral and
Maxillofacial Pathology 2nd ed, WB Saunders, Philadelphia,
PA, pp. 674-677, 2002.

97