All posts by Kamal Al-Eryani, DDS, PhD

About Kamal Al-Eryani, DDS, PhD

Kamal Al-Eryani, DDS, PhD is an Assistant Professor of Clinical Dentistry in the division of Periodontology, Diagnostic Sciences & Dental Hygiene at the Herman School of Dentistry of the University of Southern California.

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Clinical Features, Diagnosis, and Treatment of Erythema Multiforme

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Erythema multiforme (EM): First described in 1866 by Ferdinand von Hebra as an acute, self-limited cutaneous disease characterized by multiform skin lesions, now called EM minor [1]. In 1950, Bernard A. Thomas classified EM into erythema multiforme minor (von Hebra) and erythema multiforme major characterized by erosions or ulcerations involving the oral, genital, and/or ocular mucosae lesions accompanied by skin lesion seen in EM minor.

In addition to the mucosal involvement, a key difference between these two subtypes is systemic symptoms such as fever and arthralgia preceding and/or accompanying EM major.

The similarities in clinical and histopathologic findings between Erythema Multiforme Major and Stevens-Johnson Syndrome (SJS) have led to controversy over the distinction between these two mucocutaneous conditions. Historically, SJS and Toxic Epidermal Necrolysis (TEN) are considered a disease continuum of EM. In 1993 and 1995, Bastuji-Garin and colleagues proposed a new clinical classification for  EM, SJS, and TEN supporting that SJS and TEN are distinct conditions from EM [2, 3].

However, it is still firmly believed that SJS and TEN are a disease continuum. The term “erythema multiforme” should not be used to refer to SJS/TEN or vice versa. The validity of the Bastuji-Garin classification was later confirmed by a large epidemiological study [4]. Regardless of all these classifications efforts, in an analysis of 37 published cases of drug-induced EM, 24 case reports (65%) did not meet clinical criteria for EM. [5].

Bastuji-Garin, S., et al. classified EM, SJS, and TEN into five categories [3]:

  1. EM, detachment below 10% of the BSA plus localized typical targets or raised atypical targets.
  2. SJS, detachment below 10% of the BSA plus widespread macules or flat atypical targets.
  3. Overlap SJS-TEN, detachment between 10% and 30% of the BSA plus widespread macules or flat atypical targets.
  4. TEN with spots* with or without blisters, detachment above 30% of the BSA plus widespread macules or flat atypical targets.
  5. TEN without spots*, detachment above 10% of the BSA with large epidermal sheets and without any macule or target.

Spot*: EM-Likes skin lesions

Etiology:  EM etiology is divided into two main groups, infection and medication:

  1. Infections: There is strong evidence that EM is precipitated by infection (viral, bacterial, or fungal) in most cases. The most common inciting pathogen is Herpes Simplex Virus (HSV). This link between EM and HSV is evident by (i) developing EM a few weeks after an HSV infection, (ii) seropositivity for HSV antibody, and (iii) identify HSV antigen in EM patients. Mycoplasma pneumoniae infection is an important etiology to be considered for EM in children. Malignancy, autoimmune disease, sarcoidosis, menstruation, and radiation have also been reported in rare cases. With the current COVID pandemic, oral health providers need to recognize that EM-like lesions have also been observed in association with COVID-19 infection and after COVID-19 vaccination [6].
  1. Medications: It is important to understand that less than 10% of EM cases are triggered by medication such as NSAIDs, antibiotics, anticonvulsants such as Carbamazepine, and others. Medication-induced EM has contributed to the nosology controversy of EM and SJS/TEN, which is almost caused by medications. Looking carefully at the EM patient’s new medication and if there is a temporal relationship is key in identifying drug-induced EM. Identifying the offending drug is crucial in the treatment and improve the prognosis of EM. Exposure to the offending drug commonly precedes the onset of symptoms by one to four weeks, but re-exposure may result in the onset of symptoms in as little as 48 hours.


The suggested pathogenesis for HSV induces EM CD34+ cells to carry fragments of HSV DNA to the skin and mucosa where it incites a T cell‐type hypersensitivity reaction that generates interferon-γ, with the amplified immune system recruiting more T cells initiate acute inflammation causing the eruption of the EM lesions [7].

EM Clinical Findings:

The clinical course of EM varies depending on the cause. EM caused by infection is usually self-limited, resolving within a few weeks. In a minority of cases, the disease recurs over the years. Studies show that recurrent EM is mainly associated with recurrent HSV infections, which might happen two to three weeks before the EM clinical symptoms appear. As mentioned above, although less common, recurrence might happen when reexposed to an offending medication.

Regardless of the cause, EM lesions erupt within a few weeks from the infection or taking the offending medication. Skin and oral lesions appear rapidly over a few days and begin as red macules that become papular in the skin, starting primarily in the hands and moving centripetally toward the trunk in a symmetrical distribution. This acute onset of the mucocutaneous lesions is one of the hallmarks of considering EM in the differential diagnosis.

In EM Major, it is not uncommon to have a prodrome of fever, arthralgias, malaise, headache proceeding or accompany the mucocutaneous lesions. In M. pneumoniae infection-associated EM, sore throat, rhinorrhea, and cough might be seen. Although not very common, skin lesions in EM Major might present with an epidermal detachment; if the skin detachment is more than 10% of body surface area (BSA), SJS/TEN should be considered. Hence the name multiforme, skin lesions have multiple forms. The morphology of EM lesions may vary between patients and may also evolve throughout the disease stage (Early Vs. Late) in a single patient [3]:

  1. Target lesion: The stander skin lesions for EM are defined as individual lesions less than 3 cm in diameter with a regular round shape, well-defined border, and at least three different zones.
  2. Raised atypical targets: Defined as round, edematous, palpable lesions, with only two zones and/or a poorly defined border.

Interestingly, skin lesions are mostly asymptomatic; however, some patients will complain of itching or burning sensation.


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The intraoral lesion is mainly seen in EM major, not minor. The lesions range from mild erythema and erosion to large painful ulcerations covered by a yellow-white fibrinous exudate Figure 1. Lip inflammation, ulceration, and crusting are very common in patients with EM major Figure 2. It is important to understand that these lesions are not exclusive to EM and can be seen in SJS/TEN, and other conditions include Paraneoplastic Pemphigoid.

EM Minor always presents with skin lesions similar to the major subtype described above but without epidermal detachment and without or only mild mucosal disease. Also, no associated systemic symptoms accompany EM minor.

Although not included in the Bastuji-Garin classification, oral health providers must realize that sometimes EM cases present with oral mucous membrane involvement only [8].

Laboratory findings: Clinical findings and course of the disease are usually enough to diagnose patients with EM. Laboratory tests such as CBC, CMP, and CRP are not specific. Histopathologically, basal layer liquefaction and inflammatory infiltrate (includes lymphocytes, histiocytes), spongiosis, and intracellular edema. Although these histopathological features are not specific, an oral biopsy could be performed with persistent EM to assist with the exclusion of other disorders or when the diagnosis of EM is questionable. Investigational tests can be done by infectious disease specialists when the infection is considered as a possible etiology.

Diagnosis of EM Major: Diagnosis of EM Major would be appropriate in a patient with the following clinical features [3, 4]:

  • A history of recent infection strongly suggests EM. Although medications are associated with 10% of EM, medications are the leading cause of  SJS/TEN.
  • A prodrome of febrile illness and malaise can be seen in EM but not specific and can be seen more often in SJS/TEN.
  • EM mostly does not have skin detachment and, if present, is it below 10% of the BSA. On the other hand, SJS/TEN is commonly associated with skin detachment. SJS is the less severe condition comparing to TEN, in which skin detachment is <10 percent of the BSA. TEN involves detachment of >30 percent of the BSA. When skin detachment is between 10 and 30 percent of BSA, it considers overlap SJS/TEN.
  • EM is characterized by typical target-like or raised atypical targets lesions (described above). SJS/TEN lesions are commonly flat atypical targets defined as round lesions with only two zones and/or a poorly defined border, nonpalpable with the exception of a potential central blister. Also, SJS/TEN lesions might present as purpuric macules with or without blisters. In general,  blisters often occur on all or part of the SJS/TEN lesions and are rare to be seen in EM. In rare instances, TEN occurred without any discrete atypical target lesions. These cases are classified as TEN without spots.
  • While EM skin lesions are symmetrical, localized, start from the extremities, and could move centripetally, SJS and TEN are widespread, start from the neck, face, and upper torso, and can extend centrifugally.
  • Finally, comparing to SJS/TEN, recurrences are more common with EM.


  1. Review the medical history to identify the cause is crucial. If a drug is suspected, contact the prescriber physician after approval, discontinue the medication. If an infection is suspected, consider a consultation with the patient’s primary physician or infectious disease specialist for appropriate treatment of the infection.
  2. When skin is involved, always consider a dermatology consultation.
  3. The pharmacological management will depend on the severity and recurrence of the condition:
    1. Limited oral mucosal involvement: For alleviating the pain, a mouthwash containing equal parts of viscous lidocaine 2%, diphenhydramine (12.5 mg/5 mL), and aluminum hydroxide and magnesium hydroxide mixture (e.g., Maalox) as a swish-and-spit, can be used as needed, up to four times per day. Dexamethasone (0.5 mg/5 mL) oral elixir 4 times/day swish-and-spit can be used for diffused ulcers. If the ulcers are limited to a small area, fluocinonide 0.05% gel is applied two to three times per day.
    2. Extensive oral mucosal involvement: Severe oral mucous membrane involvement that prevents sufficient oral intake consider hospitalization. If hospitalization is not needed, In the first-line treatment is systemic glucocorticoids. Dosage and tapering will depend on the severity of the case and response to the treatment.  Azathioprine and dapsone have been reported helpful in several cases.
    3. An antiviral suppersion therapy, such as Acyclovir 400mg twice a day, should be considered in recurrent EM associated with HSV.

All the above medications have contraindications which the clinician has to be aware of before prescription.

figure 1








Figure 1: Intraoral erythema multiforme: Diffused ulcers covered by a yellow-white exudate/fibrinous surface. Image courtesy of Orofacial Pain and Oral Medicine Center, Herman Ostrow School of Dentistry of USC.






Figure 2:
Erythema multiforme with ulcerative, hemorrhagic crusts of the lips. Image courtesy of Orofacial Pain and Oral Medicine Center, Herman Ostrow School of Dentistry of USC.

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1. F., v.H., Atlas der Hautkrankheiten. Vienna, Austria: Kaiserliche Akademie der Wissenschaften.

2. Assier, H., et al., Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol, 1995. 131(5): p. 539-43.

3. Bastuji-Garin, S., et al., Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol, 1993. 129(1): p. 92-6.

4. Auquier-Dunant, A., et al., Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol, 2002. 138(8): p. 1019-24.

5. Roujeau, J.C., Re-evaluation of ‘drug-induced’ erythema multiforme in the medical literature. Br J Dermatol, 2016. 175(3): p. 650-1.

6. McMahon, D.E., et al., Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases. J Am Acad Dermatol, 2021. 85(1): p. 46-55.

7. Ono, F., et al., CD34+ cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM). J Invest Dermatol, 2005. 124(6): p. 1215-24.

8. Bean, S.F. and R.K. Quezada, Recurrent oral erythema multiforme. Clinical experience with 11 patients. Jama, 1983. 249(20): p. 2810-2.

Close-up Picture of a Salivary Stone in a Patient's Salivary Gland

How to Diagnose and Remove Salivary Stones (Sialoliths)

Close-up Picture of a Salivary Stone in a Patient's Salivary Gland
Figure. 1 – Sialolith in the right submandibular duct. Image courtesy of Dr. Al-Eryani, Orofacial Pain and Oral Medicine Center, Herman Ostrow School of Dentistry of USC)

What are salivary stones?

Salivary stones, also called sialoliths, are calcified organic masses that form within the salivary gland’s secretory system.  Salivary stones comprise of organic and inorganic materials, including calcium carbonates and phosphates, cellular debris, glycoproteins, and mucopolysaccharides [1]. Continue reading How to Diagnose and Remove Salivary Stones (Sialoliths)

Diagram of a CO2 Ablative Laser for Oral Laser Ablation Surgery

Oral Laser Ablation Surgery: Step-by-Step Guide for Dentists

Diagram of a CO2 Ablative Laser for Oral Laser Ablation Surgery

What is a laser?

Lasers are an intense, high energy, coherent (travels in a constant phase in time and space), monochromatic (a single wavelength particular to the medium), and collimated (travels in the same direction) electromagnetic radiation that is produced by a medium (solid, liquid, free particle, or gas).  More simply, LASER is an acronym that stands for Light Amplification by Stimulated Emission of Radiation.

Continue reading Oral Laser Ablation Surgery: Step-by-Step Guide for Dentists

Two Dentists Performing an Oral Cavity Punch Biopsy on Soft Tissue - USC Postgraduate Dentistry Master's and Certificate Programs

How to Conduct an Oral Cavity Punch Biopsy

Two Dentists Performing an Oral Cavity Punch Biopsy on Soft Tissue - USC Dentistry Online

What is a punch biopsy?

An oral cavity punch biopsy is considered the primary technique to obtain diagnostic, full thickness skin specimens.  It is performed using a circular blade or trephine attached to a pencil-like handle.  The instrument is rotated down through the epidermis and dermis, and into the subcutaneous fat.  The punch biopsy yields a cylindrical core of tissue that must be gently handled (usually with a needle) to prevent crushing the artifact at the pathologic evaluation. Continue reading How to Conduct an Oral Cavity Punch Biopsy

Dentist Performing an Excisional Oral Biopsy in a Patient's Mouth

How to Perform an Oral Biopsy

Dentist Performing an Excisional Oral Biopsy in a Patient's Mouth

A biopsy is defined as the sampling or removal of tissues or liquids from the body for examination, in order to determine the existence or cause of a disease.  A biopsy is strongly recommended for most of the lesions that persist for more than two weeks which interferes with oral function, or does not improve by removing the local irritants.

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6 Basic Etiologic Categories for an Oral Lesion

Whenever you see an oral lesion, train yourself by using the diagnostic sieve to list out possible clinical differential diagnoses:

  1. Developmental (Congenital)
  2. Inflammatory/Infection
  3. Neoplastic
  4. Traumatic
  5. Autoimmune/Allergic
  6. Oral manifestation of systemic disease

Related Reading: The Dentist’s Guide to Oral Pathology of Vesicular Ulcerative Conditions

Don’t have time to read The Dentist’s Guide to Oral Pathology of Vesicular Ulcerative Conditions?  Download the checklist!


6 Reasons Why It Is Important to Have a Differential Diagnosis

  1. It helps you determine when to perform the biopsy: Is it urgent?
  2. It helps you determine how to perform the biopsy: Punch, Incisional or Excisional biopsy? What instruments do I need?
  3. It is how doctors approach diagnosis of an unknown disease.
  4. It will demonstrate to the patient, third party, and pathologist that you have included all the clinical possibilities.
  5. It generally leads to better decision-making.
  6. It also helps to prevent errors in judgment and misdiagnosis or failure to diagnose.


What kinds of biopsies are available?

1. Punch Biopsy

Punch biopsies are commonly used in dermatology for sampling of skin lesions.  It is also used for gingival biopsies especially for cases of pemphigus vulagaris or mucous membrane pemphigoid.

2. Excisional Biopsy

An excisional biopsy removes the entire lesion and it is both a therapeutic as well as a diagnostic procedure.  Excisional biopsies are most commonly used for lesions of 1 cm or less, for even larger benign lesions to avoid multiple surgeries, or when complete removal is possible without significant morbidity.

3. Incisional Biopsy

An incisional biopsy involves taking a small portion of the lesional tissue for diagnostic purpose.  Incisional biopsies are commonly used:

  • When a lesion is large enough that definitive removal for histologic diagnosis would produce significant morbidity.
  • When necessary to convince a patient that serious pathology exists although the patient may not agree or may be asymptomatic.
  • When malignancy is highly suspected and biopsy is performed for confirmation and rapid diagnosis rather than attempting to remove the cancer completely with clear margins.

Additional Reading: Infectious Lesions of the Oral Cavity: Histoplasmosis & Mucormycosis


What are the contraindications for an oral biopsy?

There are no contraindications for a biopsy when the risk of doing nothing outweighs the risk of the surgical procedure.  In some instances, contraindications to surgical biopsy may exist due to underlying systemic conditions such as severe and uncontrolled hypertension.  In such situations, the procedure can be delayed until appropriate precautions are in place such as:

  • Asking the physician to lower the patient’s elevated blood pressure with medications.
  • Asking the physician to give the patient clotting factor or stop anticoagulant medications if the patient has an elevated INR.
  • Treating the local infection with antibiotics.
  • Referring to the adequate institute to perform the biopsy in a high risk cardiovascular disease patient (e.g. hospital).

If you are confident the lesion is a malignancy, refer to the surgeon that is likely to manage, such as head and neck surgeon or oncologist.

Note: do not try to excise a malignancy during a biopsy as there will be no lesion left for the surgeon to assess for further treatment.

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Step-by-Step Oral Biopsy Procedure

Dentist Performing an Excisional Biopsy of Oral Soft Tissue in the Mouth

1. Select the Area to Biopsy

Prior to the procedure, you must have an idea of how, where, and what kind of procedure you are going to perform.

When pemphigus vulgaris or mucous membrane pemphigoid are suspected, the biopsy should be performed at the edge of the lesion to include both lesional and normal tissues because there may not be much normal tissue left at the center of the lesion due to a very thin epithelium or ulcer.

If the lesion is a precancerous lesion like leukoplakia or an early Squamous Cell Carcinoma (SCC) then you can biopsy just the center of the lesion and leave the border alone so that the lesion can be excised in total at a future appointment.  You can also elect to biopsy a small part of the margin of the lesion and the normal tissue so that the pathologist can compare the normal and abnormal tissue.

Note: Early SCC may look like an erythroplakia or leukoplakia.

Related Reading: Oral Pathology of Oropharyngeal Squamous Cell Carcinoma


2. Prepare the Instruments and Environment

The basic instruments you need for a soft tissue biopsy include:

  1. Local anesthetic cartridge and syringe
  2. Scalpel: Blade handle with the blade or a disposable scalpel (No. 15 and 12 blades are most commonly used)
  3. Tissue forceps with and without teeth
  4. Retractors
  5. Needle holder and suture (4-0 or 5-0 silk sutures are commonly used intraorally)
  6. Scissors
  7. Gauze
  8. Curved forceps, Bite block (as needed)
  9. Specimen bottle with fixing solution and biopsy data sheet


3. Administer Anesthesia

Use both topical and local anesthesia in an attempt to obtain less or no pain to the patient during the procedure.  In general, patients are afraid and nervous for any surgical procedures.  The more pain control you achieve, the greater the chance of success.  For large lesions, anesthesia blocks are preferable.  Also, if you are planning to perform an incisional biopsy, do not infiltrate inside the lesion as that may create artifacts (vacuolation).

Do Not Rush to the Next Step

Take enough time for the local anesthesia to work.  You will not only achieve good pain control, but excellent hemostasis as well, which will ultimately make the procedure easier.


4. Make a Wedge-Shaped Incision

For both incisional and excisional biopsies, a wedge-shaped incision is desired in an attempt to have a clean, desirable closure.  The incision should extend beyond the suspected depth of the lesion.

Biopsy Incision Tips

  • If possible, include the adjacent normal tissue.
  • Do not use small strokes with the scalpel.  Incisions should be continuous.  Small strokes will destroy the cell alignment of the tissue and the orientation.
  • Do not cut the specimen to see what might be inside. The pathologist may want to ink the specimen to establish the margins.
  • For excisional biopsies, take enough representative tissue without damaging the tissue integrity.
  • Be aware of adjacent anatomy to avoid unnecessary tissue damage.
  • Be cautious not to crush the specimen with tweezers or suction the specimen. Accidental suctioning of tissue is very common. (Educate the assistant well prior to the procedure).

Note: Length of incisions should be parallel to natural resting lines when possible to optimize esthetics.

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5. Remove and Transfer the Specimen

A. Use One Bottle Per Specimen

Do not mix specimen unless it is a connective tissue mass that came out in several parts.

B. Fill with Formalin

The volume of formalin should be at least 20 times the volume of the specimen.  If immunofluorescence analysis is desired, the specimen needs to be placed in a different solution called Michel’s solution.

C. Label the Bottle

Each container should be identified with the patient’s name, clinician’s name, date and the site of the biopsy.

D. Stabilize the Tissue

Place mucosal or epithelial biopsies on a small rigid piece of paper before placing in the formalin bottle to prevent the tissue from rolling around itself and collapsing which would make it more difficult for the pathologist to orient and interpret the specimen.

E. Place an Orientation Suture (if required)

When performing a biopsy of a suspicious lesion (possible tumor), place an orientation suture in the specimen (one suture will be enough) so the pathologist can tell you which margins are clear or not.

F. Transfer to the Transport Media

Put the sample immediately into the transport media, not on gauze or on the surgical tray where it may dry out or undergo significant autolysis, and make sure the cap is tight so it does not spill while being transported to the pathology lab.

G. Fill out the Biopsy Data Sheet

Provide the pathologist with clinical and background information including: clinical appearance, duration, symptoms, pertinent medical history, risk factors, and clinical differential diagnosis.

If possible, submit copies of clinical or radiographic images with the biopsy to give the pathologist the ability to correlate clinical, radiographic, and histopathologic findings.

Lastly, do not draw on or circle the lesion on photographs or radiographs.  The pathologist will be able to see the abnormality without you pointing it out and possibly distorting the image.


6. Obtain Hemostasis and Wound Closure

Best hemostasis can be obtained by direct pressure unless you damaged a larger vessel.

For patients who will definitely need follow-up, use non-resorbable silk sutures.  One suture should be placed every 3-5mm’s, and the wound should be sutured without tension to avoid dehiscence.  Similarly, do not pull the knot too tight for soft tissue suturing.

Note: Do not try to achieve hemostasis by using anesthesia.


7. Provide Post-operative Instructions

Review the aftercare instructions with the patient and preferably a family member to ensure adherence and understanding.

A. Pain

If the procedure site was large or if the patient is already experiencing pain, prescribe NSAIDs or stronger analgesics (e.g. Vicodin).  For small procedures, patient can take OTC analgesics such as a 200-mg tablet of Ibuprofen (Advil, Motrin) 3 times a day with food, or a 325-mg tablet of Acetaminophen (Tylenol) every 6 hours, or as needed.

For any biopsy, instruct the patient to take one tablet of analgesic before the anesthesia wears-off.  If you do not hold any analgesics in your office, you should advise the patient to bring in the medication which they usually take when they have pain at the day of biopsy.

B. Bleeding

Bleeding might occur especially during the first few days: Patient can apply direct pressure for 10 minutes using a gauze or tissue to stop bleeding. If it continues to bleed, instruct patient to contact the clinic.

C. Swelling and Bruising

Swelling can happen as a healing process. Educate the patient that peak swelling is generally the 3rd or 4th day after the procedure and then will gradually subside. Bruising is less common for soft tissue biopsies, but might happen depending on the extent of the procedure and the patient’s age (e.g. older) or immunity.

D. Smokers

For smokers, educate them to stop smoking during the time when tissue is healing (at least a week).

E. Additional Biopsies

Lastly, inform the patient the possibility of another biopsy in the future depending on the diagnosis the pathologist makes.  If the histologic diagnosis does not seem correct with your clinical impression, talk to the pathologist personally and decide if you need another biopsy or not.


Further Reading


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