Oral Ulceration & Vesiculobullous diseases

LAB 2 Dr. Tahani Abualteen

Definition: Ulcer = localized defect in the surface epithelium exposing the underlying connective tissue base leading to inflammation Most common lesion of the oral mucosa

May be a manifestation of many disease entities (local and general disorders)

Erosion = superficial ulcer (partial loss of epithelial thickness not exposing the connective tissue base)

Causes of oral ulceration: Infective (viral, bacterial, fungal)

Traumatic (mechanical, chemical, thermal, factitious injury, radiation, eosinophilic ulcer "traumatic granuloma")
Idiopathic (recurrent aphthous stomatitis "major, minor, herpetiform") Neoplastic (SCC, other malignant neoplasms) Associated with systemic diseases (GIT diseases, hematological diseases, Behcets disease, HIV infection) Associated with dermatologic diseases (lichen planus, chronic discoid lupus erythematosus, vesiculobullous diseases)

** All these should be kept in mind as differential diagnoses for ulcers

Traumatic Ulceration

Mechanical Ulceration
Three criteria for diagnosis 1. Define a cause 2. Fit size, shape and location of ulcer 3. Healing within 10 days of cause removal Chronic ulcers: Deep crater like ulcer with rolled everted margins and Induration Differentiation of chronic traumatic ulcers from a neoplastic ulcer may be difficult When is biopsy indicated?!

If we remove the cause and the presumed chronic traumatic ulcer does NOT show signs of healing within a period of 10-14 days

Chronic Traumatic Ulcer

Chemical Ulceration
Highly concentrated or caustic materials used in dental practice (e.g. hydrogen peroxide) that may be accidentally applied to oral mucosa or preparations used by patients in self-treatment of oral complaints (e.g. local use of aspirin to relieve toothache, inadequately diluted mouth washes) Reaction varies in severity (edema to necrosis), so the concentration and duration of the irritant is important Recall: oLow-grade chronic irritation hyperplasia or hyperkeratosis oHigh-grade or severe acute trauma ulceration or necrosis

Aspirin Burn
Caustic action of aspirin is dose and time related Reactions vary in severity from edema of epithelium (resembling Leukoedema) to necrosis of epithelium (presenting as white patches which slough off leaving areas of ulceration) Painful

Patients history and location of the lesion are important for clinical diagnosis

Formocresol Burn

Hydrogen peroxide burn

Anesthetic necrosis

NOT clearly understood! May be due to tissues being stretched or damaged by giving too much solution Or due adrenaline which is a vasoconstrictor in anesthetic solutions

Factitious ulcers

Self-inflicted ulcers (induced on purpose!) May be a manifestation of stress, anxiety, or more severe emotional disturbance

Factitious ulceration and keratosis

Factitious ulcers

Radiation Ulcers
In patients undergoing radiotherapy for head and neck cancer, the oral mucosa may suffer from: Damage to the epithelium (resulting in Erythema, radiation mucositis, and ulceration) Damage to blood vessels (resulting in epithelial atrophy) Damage to lymphatics (resulting in edema) Thin atrophic epithelium is prone to traumatic ulcers

Differentiation of radiation ulcers form neoplastic ulcers may be difficult but radiation ulcers (mucositis) are generally painful while pain is not a common feature of early malignant disease

SCC

Radiation mucositis

????

The patient stated that he had a very severe severing injury to the site of the lesion 3 days earlier
Upon microscopy, the lesion is found to be infiltrated with Eosinophils and histiocytes

Eosinophilic Ulcer
Etiology: chronic trauma and crush injury to skeletal muscles Occurs most commonly in the tongue Clinical appearance: chronic, well-demarcated ulcer which may mimic Sequamous cells carcinoma ulcer (indurated and fixed due to histiocytes infiltration) Histopathological features Dense chronic inflammatory cell infiltrate in the base of the ulcer involving underlying damaged muscle Deeper parts of the lesion are characterized by an infiltrate rich in histiocytes & Eosinophils True granulomas aren't present and the condition has no relation to eosinophilic granuloma of bone Treatment: remove the cause and follow-up to see signs of healing

Healing upon Follow Up

????

????

????

The Patient states frequent recurrences and also local Prodromal symptoms of tingling and burning sensation 1-2 days before the eruption of the lesion

Diagnosis??

Clinical Diagnosis: Recurrent aphthous stomatitis, exacerbated by orthodontic appliances

Minor RAS
Accounts for 80% of RAS 1-5 ulcers (that are shallow, round or oval, with grey/yellow base and an erythematous margin) Affect non keratinized mucosa Less than 10 mm in diameter Heal without scarring within 10 days Recur in 1-4 month intervals

Major RAS
1-10 ulcers Affect any area in the mouth (keratinized & non-keratinized mucosa) ** Common sites: lips, soft palate, tonsils, oropharynx Greater than 10 mm in diameter Heal with scarring within 4-6 weeks

Major RAS
Recur in less than 1 month (in severe cases, ulceration of the oral cavity is continuous and may be associated with severe discomfort and with difficulty in eating & speaking) Extends deeper than the shallow minor aphthae and may present as crater-like ulcer with rolled everted margins and Induration on palpation ** Differentiation of isolated major aphthous ulcer from a neoplastic ulcer may be difficult

Major RAS-scarring

Herpetiform RAS
The least common Affects older age group Hundreds of small pin point ulcers resembling herpetic ulcers Affect any area in the mouth (keratinized & non-keratinized mucosa) 1-2 mm in diameter When several ulcers are clustered together, coalescence can result in larger areas of ulceration of irregular outline Heal in 2-3 weeks (large coalesced ulcers may take longer time to heal and may heal with scarring) Recur in less than 1 month (in severe cases, ulceration of the oral cavity is continuous and may be associated with severe discomfort and with difficulty in eating & speaking)

Herpetiform Aphthae

Etiology of RAS:

Most likely immune mediated (there is increasing evidence that damaging immune responses are involved)
A number of Co factors (local and general factors) may play a contributory role in a proportion of cases

Pathogenesis of RAS:
Epithelial destruction is most likely the result of T-cell mediated cytotoxicity Epithelial antigen(s) which are responsible for triggering the immune response leading to the Cytotoxic damage remain unknown However, it is suggested that immune mediated damage may be due to cross-reactivity between streptococcal protein antigens and epithelial plasma membrane proteins ** In susceptible individuals, the host's immune response to streptococcal antigens may also damage the oral epithelium T cell mediated cytotoxicity: CD4 + T cells predominate in the pre-ulcerative phase CD8+ Cytotoxic T cells predominate ulcerative phase CD4 + T cells predominate in the healing phase

Histopathological features
In the pre-ulcerative stage, there is infiltration of the lamina propria by lymphocytes Small number of lymphocytes also infiltrate the epithelium As the ulcerative stage approaches, there's increased infiltration of the tissues by lymphocytes (especially the epithelium) associated with damage to epithelial cells leading eventually to their death and the formation of an ulcer

In the healing phase, the number of lymphocytes decreases

Histopathological finding

epithelium

Loss of surface epithelium

Inflammatory infiltrate

Diagnosis of RAS?!
Clinical features (site, number, history of recurrence, family history)

Histopathological features (non-specific to RAS)

Recurrent Aphthous Stomatitis Treatment

Steroids
Topical* Systemic Intralesional

Recurrent Aphthous Stomatitis Management

Triamcinolone acetonide 0.1% aqueous suspension, mouthrinse and expectorate QID, No food or drink until hour after use Clobetasol 0.05% ointment, apply thin film to oral ulcers QID, No food or drink until hour after use Use only Biotene toothpaste SLS (Sodium Lauryl Sulphate) can induce aphthous ulcers Advised to contact you in 2 weeks to report on condition

This patient has history of recurrence of these lesions Not only the oral mucosa is affected but also the skin and the eyes

A sterile papule developed 1 day after injecting the same site with normal saline

Diagnosis??
Behcet's Syndrome

What is your differential diagnosis?!?!

Chronic ulcer with rolled everted margins and Induration on palpation?!?

Differential Diagnosis of Chronic Oral Ulcerative Lesions

Sequamous cell carcinoma Deep fungal infection
Histoplasmosis, cryptococcosis, mucormycosis

Chronic viral infection

Herpes simplex, cytomegalovirus

Oral tuberculosis Trauma

Eosinophilic ulcer, factitious ulcer

Syphilis Major aphthous

Vesiculobullous diseases
Diseases that result in collection of clear fluid (blisters) within or below the epithelium

Blisters are classified into (vesicles and bullae)

Vesicles: Fluid filled lesion Smaller in size Mostly arise intra-epithelially Bullae: Fluid filled lesion Larger in size Mostly arise sup- epithelially Vesiculobullous diseases are present as oral ulceration following rupture of the vesicles & bullae

Classification of vesiculobullous diseases

Vesiculobullous diseases are classified into 2 major groups depending on the histological location of the lesions: Intraepithelial vesiculobullous diseases (lesions form within the epithelium) Pemphigus Vulgaris (Acantholytic) Herpes Simplex infection (Non-acantholytic) Subepithelial vesiculobullous diseases (lesions form between the epithelium & lamina propria) Pemphigoid Erythema multiforme Dermatitis herpetiformis Linear IgA disease Epidermolysis bullosa Angina bullosa hemorrhagica (oral blood blisters) Bullous lichen planus

31 YEAR OLD MAN

Chief Complaint
Oral discomfort since 1 week Sudden onset Recurrences with complete remission after Sometimes Entire mouth and throat, conjunctiva & skin involved

Medical History: No abnormalities

Diagnosis??
Erythema Multiforme

oTarget "iris" lesions consist of concentric rings of varying Erythema, in the center of which may be an intact or ruptured and crusted bulla

oCharacteristic diagnostic Feature oHands & Feet

Erythematous patches are quickly followed by vesiculobullous eruptions which rapidly breakdown into erosions as the bullae disintegrate
Erosions on the lips are associated with bleeding and crusting Circumoral crusting hemorrhagic lesions are an important sign to reach clinical diagnosis

Erythema Multiforme
Wide range of clinical presentation Maculopapular, vesiculobullous, target Iris lesions Orally: lips and anterior parts

Target

Erythema Multiforme
Sudden onset

Skin and mucous membranes

Pathogenesis is not clear
Hypersensitivity rxn, type 3 hypersensitivity
And consequenses

Ag - Ab complexes have been detected in EM and HSV infn

Precipitating factors include

Drugs: sulphonamides, penicillin Viral infections: herpes simplex infection (Recurrent Erythema multiforme is associated in particular with recurrent attacks of herpes simplex virus infection) Spontaneously

Erythema Multiforme clinical features

Young adults Male >female Prodromal symptoms +,Recurrent Severity varies: Oral lesions with or without skin lesions Skin lesions alone
Subside in 10-14 days

Severe form: Steven Johnson syndrome: skin, mucosal surfaces and conjunctiva lesions

Erythema Multiforme
Microscopic features: not diagnostic Diagnosis is primarily clinical No autoantibodies, so negative direct & indirect immunoflourescence Treatment and prognosis
Remove causative drugs, if any Topical and systemic corticosteroids May be recurrent May benefit from prophylactic acyclovir

 54 years old man Chronic gingivitis, 18 months duration

Clinical diagnosis for the gingival condition?!

Desquamative gingivitis

What are your differential diagnoses?

1- Mucous membrane Pemphigoid 2- Pemphigus Vulgaris 3- Erosive lichen planus 4- Allergic reaction 5- Drug Induced

Gentle lateral pressure by blunt instrument induced bullous formation/ Nikolsky's sign

Biopsy was taken

Epithelium

Subepithelial seperation

What are your differential diagnoses?

1- Mucous membrane Pemphigoid 2- Erythema Multiforme 3- Linear IgA disease 4- Dermatitis Herpetiformis 5- Epidermolysis Bullosa 6- Angina Bullosa Hemorrhagica 7- Bullous lichen planus

Immunoflourescence was done .

Epithelium

IgG deposition and C3

Diagnosis??
Mucous membrane Pemphigoid

Pemphigoid
Autimmune disease
Auto antibodies to hemidesmosomes and basement membrane

Separation is subepithelial Several different Ag are recognized

Pemphigoid
2 clinical groups: Mucous membrane Pemphigoid
Mainly mucosal

Bullous Pemphigoid
Mainly skin

MUCOUS MEMBRANE (CICATRICIAL) PEMPHIGOID

Etiology: antibodies against BP Ag2
Women>men Tense bullae

Oral Lesions of Mucous Membrane Pemphigoid

Heal with scarring (cicatritial)
90% involve gingiva, Chronic desquamative gingivitis may be the only oral manifestation Nikolsky's sign

MMP

MMP

MMP

MUCOUS MEMBRANE PEMPHIGOID: MICROSCOPIC Subepithelial vesicle

No subepithelial inflammation first Later, inflammation and perivascular infiltrate Eosinophils are involved Release of proteases

MUCOUS MEMBRANE PEMPHIGOID

Diagnosis: Direct immunoflourescence (linear deposition of IgG and C3 in the basement membrane) Indirect immunoflourescence using modern techniques (autoantibodies can now be detected in the serum of about 80% of patients )

MUCOUS MEMBRANE PEMPHIGOID

Treatment: topical and/or systemic corticosteroids Prognosis: good, but monitor eye lesions

What if this was your biopsy results?

Intraepithelial separation

Basal epithelial layer Connective tissue

And this was your Immunoflourescence results?

epithelium

IgG and C3

Diagnosis??
Pemphigus Vulgaris

Pemphigus
Vulgaris is the most common type Female more than male Ethnic groups: Ashkenazi Jews

Pemphigus
Pathogenesis: auto Ab against desmosomes
Desmoglein 3 Desmoglein 1 and 3 in skin and oral Activation of proteinases

Pemphigus Vulgaris

Pemphigus Vulgaris

Pemphigus vulgaris
Bullous eruptions: skin and mucous membranes

Intraepithelial
Oral mucosa is almost always involved Fragile bullae Any part of the oral mucosa may be involved, soft palate, buccal mucosa and lips
Desquamative gingivitis

Pemphigus vulgaris
Direct immunoflourescence:
biopsy from peri-lesional tissue IgG autoantibodies can be detected within the epithelial thickness producing a characteristic fish-net pattern

Indirect immunoflourescence
Disease monitoring Autoantibodies to desmosomes Titer correlates with severity Not present in early stages? Or all patients

Pemphigus vulgaris
Histopathology Intra epithelial separation Little subepithelial inflammation Tzanck cells

Multiple Skin vesiculobullous lesions

What are your differential diagnoses?

1- Bullous Pemphigoid 2- Erythema Multiforme 3- Linear IgA disease 4- Dermatitis Herpetiformis 5- Epidermolysis Bullosa

Immunoflourescence was done .

granular deposition of IgA at BM

Diagnosis?
Dermatitis Herpetiformis

Dermatitis Herpetiformis
Autoimmune disease Subepithelial blistering Primarily skin disease, oral manifestation variable
Small Erythema to wide necrosis

90% associated with gluten hypersensitivity

Dermatitis Herpetiformis
Biopsy shows: subepithelial separation & granular accumulation of neutrophils Direct immunoflourescence shows: Granular deposition of IgA & C3 in the basement membrane Indirect immunoflourescence: negative

What if this was your Immunoflourescence results? ?

Subepithelial separation

Linear deposition of IgA at BM

Diagnosis?
Linear IgA disease

Linear IgA Disease

Rare autoimmune disease of skin and occasionally oral. Histopathology: subepithelial seperation D/D: dermatitis herpetiformis and MMP Immunofluorescence: linear IGA along basement memnrane Gluten hypersensitivity in 30%

If this has been going on since birth???

Extreme fragility of the skin Bullae usually develop in response to minimal trauma or pressure but they may arise spontaneously

Claw-like deformity of the hands

LIMITED MOUTH OPENING

Bullae rupture to leave painful erosions and subsequent scarring can restrict the opening of the mouth, movement of lips and tongue

What is your clinical diagnosis? Epidermolysis Bullosa

Epidermolysis Bullosa
Complex group of syndromes Gene mutations coding for keratins in basal layer or collagens Keratin: intraepithelial bullae Basement membrane : subepithelial bullae

TYPES OF EPIDERMOLYSIS BULLOSA

SIMPLEX: localized skin lesions; oral lesions, good prognosis DYSTROPHIC DOMINANT: nails; oral lesions; scarring; fair prognosis DYSTROPHIC RECESSIVE: severe skin and oral lesions, scarring, abnormal teeth, poor prognosis JUNCTIONAL: severe skin and oral lesions, abnormal teeth, fatal

Epidermolysis Bullosa
Clinically: at birth Extreme fragility of skin Heal slowly with scarring Several types are incompatible with life

Restricted mouth opening Rampant caries

EPIDERMOLYSIS BULLOSA
Treatment
Avoid trauma Antibiotics, corticosteroids Prognosis Simplex: good Recessive & Junctional: fatal

If this happened in adulthood What would be your diagnosis?!?!?!

What is your clinical diagnosis? Epidermolysis Bullosa aquista

Epidermolysis Bullosa Aquisita

Autoimmune disease Linear deposition of IgG and C3 in the basement membrane zone