Common Vesiculobullous Diseases Etiology,Clinical Presentation,Microscopic findings,Diagnosis,Differential diagnosis and Treatment

Epidermolysis Bullosa

Etiology

• A diverse group of predominantly cutaneous, but also mucosal, mechanobullous diseases

• Inherited form: autosomal dominant or recessive patterns may occur

• Acquired form (acquisita): autoimmune from autoantibodies (immunoglobulin G [IgG]) to type VII collagen deposited within the basement membrane zone and upper dermis or lamina propria

Clinical Presentation

• Variable, depending upon the specific form of many subtypes recognized

• Mucosal lesions range in severity from mild to debilitating, depending on subtype:

• Inherited forms have wide range of oral mucosal involvement, with most severe form (autosomal recessive, dermolytic) also demonstrating enamel hypoplasia and caries

• Acquisita form with mucous membrane pemphigoid variant shows oral and conjunctival erosions/blisters

• Mucosal involvement absent in several variants

• Scarring and stricture formation common in severe recessive forms

• Mucosa is often friable, but it may be severely blistered, eroded, or ulcerated.

• Loss of oral anatomic landmarks may follow severe scarring (eg, tongue mucosa may become smooth and atrophic with episodes of blistering and scarring).

• Obliteration of vestibules, reduction of oral opening, ankyloglossia

• Scarring can be associated with atrophy and leukoplakia, with increased risk for squamous cell carcinoma development.

Microscopic Findings

• Bullae vary in location depending upon the form that is present:

• Intraepithelial in nonscarring forms

• At epithelial–connective tissue junction in dystrophic forms

• Subepithelial/intradermal in scarring forms

• Ultrastructural findings are as follows:

• Intraepithelial forms associated with defective cytokeratin groups

• Junctional forms associated with defective anchoring filaments at hemidesmosomal sites (epithelial–connective tissue junction)

• Dermal types demonstrate anchoring fibril or collagen destruction.

Diagnosis

• Distribution of lesions

• Family history

• Microscopic evaluation

• Ultrastructural evaluation

• Immunohistochemical evaluation of basement membrane zone using specific labeled antibodies as markers for site of blister formation

Differential Diagnosis

• Varies with specific form

• Generally includes the following:

• Bullous pemphigoid

• Mucous membrane (cicatricial) pemphigoid

• Erosive lichen planus

• Dermatitis herpetiformis

• Porphyria cutanea tarda

• Erythema multiforme

• Bullous impetigo

• Kindler syndrome

• Ritter’s disease

Treatment

• Acquisita form:

• Some recent success with colchicine and dapsone

• Immunosuppressive agents including azathioprine, methotrexate, and cyclosporine may be effective

• Acquisita and inherited forms:

• Avoidance of trauma

• Dental prevention strategies including extra-soft brushes, daily topical fluoride applications, dietary counseling

Prognosis

• Widely variable depending on subtype

Erythema Multiforme

Etiology

• Many cases preceded by infection with herpes simplex; less often with Mycoplasma pneumoniae or other organisms

• May be related to drug consumption, including sulfonamides, other antibiotics, analgesics, phenolphthalein-containing laxatives, barbiturates

• Another trigger may be radiation therapy.

• Essentially an immunologically mediated reactive process, possibly related to circulating immune complexes

Clinical Presentation

• Acute onset of multiple, painful, shallow ulcers and erosions with irregular margins

• Early mucosal lesions are macular, erythematous, and occasionally bullous.

• May affect oral mucosa and skin synchronously or metachronously

• Lips most commonly affected with eroded, crusted, and hemorrhagic lesions (serosanguinous exudate) known as Stevens-Johnson syndrome when severe

• Predilection for young adults

• As many as one-half of oral cases have associated erythematous to bullous skin lesions.

• Target or iris skin lesions may be noted over extremities.

• Genital and ocular lesions may occur.

• Usually self-limiting; 2- to 4-week course

• Recurrence is common.

Diagnosis

• Appearance

• Rapid onset

• Multiple site involvement in one-half of cases

• Biopsy results often helpful, but not always diagnostic

Differential Diagnosis

• Viral infection, in particular, acute herpetic gingivostomatitis (Note: Erythema multiforme rarely affects the gingiva.)

• Pemphigus vulgaris

• Major aphthous ulcers

• Erosive lichen planus

• Mucous membrane (cicatricial) pemphigoid

Treatment

• Mild (minor) form: symptomatic/supportive treatment with adequate hydration, liquid diet, analgesics, topical corticosteroid agents

• Severe (major) form: systemic corticosteroids, parenteral fluid replacement, antipyretics

• If evidence of an antecedent viral infection or trigger exists, systemic antiviral drugs during the disease or as a prophylactic measure may help.

• See “Therapeutics” section for details.

Prognosis

• Generally excellent

• Recurrences common

 

Hand-Foot-and-Mouth Disease

Etiology

• A very common enterovirus infection (coxsackievirus A10 or A16), which may occur in mild epidemic proportion, chiefly in children

• Incubation period is short, usually less than 1 week

Clinical Presentation

• Oral mucosal lesions with focal herpes simplex–like appearance, usually involving nonkeratinized tissue (soft palate, floor of mouth, labial-buccal mucosa)

• Accompanying palmar, plantar, and digital lesions are deeply seated, vesicular, and erythematous

• Short course with mild symptoms

Diagnosis

• Concomitant oral and cutaneous lesions

• Skin lesions commonly involve hands and feet.

• Skin lesions may involve buttocks.

• Antibody-titer increase measured between acute and recovery phases

Differential Diagnosis

• Herpangina

• Herpes simplex infection

• Acute lymphonodular pharyngitis

Treatment

• Symptomatic treatment only

• Patient should be cautioned against the use of aspirin to manage fever.

Prognosis

• Excellent

• Lifelong immunity, but it is strain specific

Herpangina

Etiology

• Most often by members of coxsackievirus group A (7, 9, 10, and 16) or group B (1–5)

• Occasionally due to echovirus 9 or 17

Clinical Presentation

• Incubation period of 5 to 9 days

• Acute onset

• Usually endemic in young children; usually occurs in summer

• Often subclinical

• Posterior oral cavity, tonsillar pillars involved

• Macular erythematous areas precede short-lived vesicular eruption, followed by superficial ulceration

• Accompanied by pharyngitis, dysphagia, fever, malaise, headache, lymphadenitis, and vomiting

• Self-limiting course, usually under 2 weeks

Diagnosis

• Other viral illnesses to be ruled out or separated

• Course, time of year, location of lesions, contact with known infected individual

Differential Diagnosis

• Hand-foot-and-mouth disease

• Varicella

• Acute herpetic gingivostomatitis

Treatment

• Soft diet

• Hydration

• Antipyretics

• Chlorhexidine rinses

• Compounded mouth rinses

Prognosis

• Excellent

Herpetic Stomatitis: Primary

Etiology

• Herpes simplex virus (HSV)

• Over 95% of oral primary herpes due to HSV-1

• Physical contact is mode of transmission

Clinical Presentation

• 88% of population experience subclinical infection or mild transient symptoms

• Most cases occur in those between 0.5 and 5 years of age.

• Incubation period of up to 2 weeks

• Abrupt onset in those with low or absent antibody to HSV-1

• Fever, anorexia, lymphadenopathy, headache, in addition to oral ulcers

• Coalescing, grouped, pinhead-sized vesicles that ulcerate

• Ulcers show a yellow, fibrinous base with an erythematous halo

• Both keratinized and nonkeratinized mucosa affected

• Gingival tissue with edema, intense erythema, pain, and tenderness

• Lips, perioral skin may be involved

• 7- to 14-day course

Diagnosis

• Usually by clinical presentation and pattern of involvement

• Cytology preparation to demonstrate multinucleate virusinfected giant epithelial cells

• Biopsy results of intact macular area show intraepithelial vesicles or early virus-induced epithelial (cytopathic) changes

• Viral culture or polymerase chain reaction (PCR) examination of blister fluid or scraping from base of erosion

Differential Diagnosis

• Herpangina

• Hand-foot-and-mouth disease

• Varicella

• Herpes zoster (shingles)

• Erythema multiforme (typically no gingival lesions)

Treatment

• Soft diet and hydration

• Antipyretics (avoid aspirin)

• Chlorhexidine rinses

• Systemic antiviral agents (acyclovir, valacyclovir) if early in course or in immunocompromised patients

• Compounded mouth rinse

Prognosis

• Excellent in immunocompetent host

• Remission/latent phase in nearly all those affected who have adequate antibody titers

Impetigo

Etiology

• Cutaneous bacterial infection: Streptococcus and Staphylococcus species

• Is spread through direct contact

• Highly contagious

Clinical Presentation

• Honey-colored, perioral crusts preceded by vesicles

• Flaccid bullae less common (bullous impetigo)

Diagnosis

• Clinical features

• Culture of organism (usually group A, â-hemolytic streptococci or group II Staphylococcus aureus)

• Herpes simplex (recurrent)

• Exfoliative cheilitis

• Drug eruptions

• Other vesiculobullous diseases

Treatment

• Topical antibiotics (mupirocin, clindamycin)

• Systemic antibiotics

Prognosis

• Excellent

• Rarely, poststreptococcal glomerulonephritis may develop.

Mucous Membrane Pemphigoid

Etiology

• Autoimmune; trigger unknown

• Autoantibodies directed against basement membrane zone antigens

Clinical Presentation

• Vesicles and bullae (short lived) followed by ulceration

• Multiple intraoral sites (occasionally gingiva only)

• Usually in older adults

• 2:1 female predilection

• Ocular lesions noted in one-third of cases

• Proclivity for scarring in ocular, laryngeal, nasopharyngeal, and oropharyngeal tissues

Microscopic Findings        

• Subepithelial cleft formation

• Linear pattern IgG and complement 3 (C3) along basement membrane zone; less commonly IgA

• Direct immunofluorescence examination positive in 80% of cases

• Indirect immunofluorescence examination usually negative

• Immunoreactants deposited in lamina lucida in most patients

Diagnosis

• Biopsy

• Direct immunofluorescent examination

Differential Diagnosis

• Pemphigus vulgaris

• Erythema multiforme

• Erosive lichen planus

• Lupus erythematosus

• Epidermolysis bullosa acquisita

Treatment

• Topical corticosteroids

• Systemic prednisone, azathioprine, or cyclophosphamide

• Tetracycline/niacinamide

• Dapsone

• See “Therapeutics” section for details.

Prognosis

• Morbidity related to mucosal scarring (oropharyngeal, nasopharyngeal, laryngeal, ocular, genital)

• Management often difficult due to variable response to corticosteroids

• Management often requires multiple specialists working in concert (dental, dermatology, ophthalmology, otolaryngology)

Paraneoplastic Pemphigus

Etiology

• Autoimmune, triggered by malignant or benign tumors

• Autoantibodies directed against a variety of epidermal antigens including desmogleins 3 and 1, desmoplakins I and II, and other desmosomal antigens, as well as basement membrane zone antigens

Clinical Presentation

• Short-lived vesicles and bullae followed by erosion and ulceration; resembles oral pemphigus

• Multiple oral sites

• Severe hemorrhagic, crusted erosive cheilitis

• Painful lesions

• Cutaneous lesions are polymorphous; may resemble lichen planus, erythema multiforme, or bullous pemphigoid

• Underlying neoplasms such as non-Hodgkin’s lymphoma, leukemia, thymoma, spindle cell neoplasms, Waldenström’s macroglobulinemia, and Castleman’s disease

Microscopic Findings

• Suprabasilar acantholysis, keratinocyte necrosis, and vacuolar interface inflammation

• Direct immunofluorescent testing is positive for epithelial cell surface deposition of IgG and C3 and a lichenoid tissue reaction interface deposition pattern

• Indirect immunofluorescent testing is positive for epithelial cell surface IgG antibodies

• Special testing with mouse and rat bladder, cardiac muscle, and liver may demonstrate paraneoplastic pemphigus antibodies that bind to simple columnar and transitional epithelia

Diagnosis

• Biopsy of skin or mucosa

• Direct immunofluorescent examination of skin or mucosa

• Indirect immunofluorescent examination of sera including special substrates

Differential Diagnosis

• Pemphigus vulgaris

• Erythema multiforme

• Stevens-Johnson syndrome

• Mucous membrane (cicatricial) pemphigoid

• Erosive oral lichen planus

Treatment

• Identification of concurrent malignancy

• Immunosuppressive therapy

Prognosis

• Good with excision of benign neoplasms

• Grave, usually fatal, with malignancies

• Management is very challenging.

Pemphigus Vulgaris

Etiology

• An autoimmune disease where antibodies are directed toward the desmosome-related proteins desmoglein 3 or desmoglein 1

• A drug-induced form exists with less specificity in terms of immunologic features, clinical presentation, and histopathology

Clinical Presentation

• Over 50% of cases develop oral lesions as the initial manifestation

• Oral lesions develop in 70% of cases

• Painful, shallow irregular ulcers with friable adjacent mucosa

• Nonkeratinized sites (buccal, floor, ventral tongue) often are initial sites affected

• Lateral shearing force on uninvolved skin or mucosa can produce a surface slough or induce vesicle formation (Nikolsky sign)

Microscopic Findings

• Separation or clefting of suprabasal from basal layer of epithelium

• Intact basal layer of surface epithelium

• Vesicle forms at site of epithelial split

• Nonadherent spinous cells float in blister fluid (Tzanck cells)

• Direct immunofluorescence examination positive in all cases

• IgG localization to intercellular spaces of epithelium

• C3 localization to intercellular spaces in 80% of cases

• IgA localization to intercellular spaces in 30% of cases

• Indirect immunofluorescence examination positive in 80% of cases

• General correlation with severity of clinical disease

Diagnosis

• Clinical appearance

• Mucosal manifestations

• Direct/indirect immunofluorescent studies

Differential Diagnosis

• Mucous membrane (cicatricial) pemphigoid

• Erythema multiforme

• Erosive lichen planus

• Drug reaction

• Paraneoplastic pemphigus

Treatment

• Systemic immunosuppression

• Prednisone, azathioprine, mycophenolate mofetil, cyclophosphamide

• Plasmapheresis plus immunosuppression

• IVIg for some recalcitrant cases

• See “Therapeutics” section for details.

Prognosis

• Guarded

• Approximately a 5% mortality rate secondary to long-term systemic corticosteroid–related complications

Recurrent Herpetic Stomatitis: Secondary

Etiology

• Herpes simplex virus

• Reactivation of latent virus

Clinical Presentation

• Prodrome of tingling, burning, or pain at site of recurrence

• Multiple, grouped, fragile vesicles that ulcerate and coalesce

• Most common on vermilion border of lips or adjacent skin

• Intraoral recurrences characteristically on hard palate or attached gingiva (masticatory mucosa)

• In immunocompromised patients, lesions may occur in any oral site and are more severe (herpetic geometric glossitis).

Diagnosis

• Characteristic clinical presentation and history

• Viral culture or PCR examination of blister fluid or scraping from base of erosion

• Cytologic smear

• Direct immunofluorescence examination of smear

Differential Diagnosis

• Erythema multiforme

• Herpes zoster (shingles)

• Herpangina

• Hand-foot-and-mouth disease

Treatment

• Acyclovir or valacyclovir early in prodrome

• Supportive

• Acyclovir may be used for prophylaxis for seropositive transplant patients

• Ganciclovir may be used for human immunodeficiency virus (HIV)-positive patients, especially those co-infected with cytomegalovirus.

• For recurrent herpes labialis, see “Therapeutics” section.

Prognosis

• Excellent

• Healing without scarring within 10 to 14 days

• Protracted healing in HIV-positive patients

Stevens-Johnson Syndrome

Etiology

 • A complex mucocutaneous disease affecting two or more mucosal sites simultaneously

• Most common trigger: antecedent recurrent herpes simplex infection

• Infection with Mycoplasma also may serve as a trigger.

• Medications may serve as initiators in some cases.

• Sometimes referred to as “erythema multiforme major”

Clinical Presentation

• Labial vermilion and anterior portion of oral cavity usually affected initially

• Early phase is macular followed by erosion, sloughing, and painful ulceration

• Lip ulcers appear crusted and hemorrhagic.

• Pseudomembrane; foul-smelling presentation as bacterial colonization supervenes

• Posterior oral cavity and oropharyngeal involvement leads to odynophagia, sialorrhea, drooling

• Eye (conjunctival) involvement may occur.

• Genital involvement may occur.

• Cutaneous involvement may become bullous.

• Iris or target lesions are characteristic on skin.

Microscopic Findings

• Subepithelial separation with basal cell liquefaction

• Intraepithelial neutrophils

• Epithelial and connective tissue edema

• Perivascular lymphocytic infiltrate

Diagnosis

• Usually made on clinical grounds

• Histopathology is not diagnostic.

Differential Diagnosis

• Pemphigus vulgaris

• Paraneoplastic pemphigus

• Mucous membrane (cicatricial) pemphigoid

• Bullous pemphigoid

• Acute herpetic gingivostomatitis

• Stomatitis medicamentosa

Treatment

• Hydration and local symptomatic measures

• Topical compounded oral rinses

• Systemic corticosteroid use controversial

• Recurrent, virally associated cases may be reduced in frequency with use of daily, low-dose antiviral prophylactic therapy (acyclovir, famciclovir, valacyclovir).

• May require admission to hospital burn unit

Prognosis

• Good; self-limiting usually

• Recurrences not uncommon

Varicella and Herpes Zoster

Etiology

• Primary and recurrent forms due to varicella-zoster virus (VZV)

• Primary VZV (chickenpox): a childhood exanthem

• Secondary (recurrent) VZV (herpes zoster/shingles) infection: most common in elderly or immunocompromised adults

Clinical Presentation

• Varicella (chickenpox)

• Fever, headache, malaise, and pharyngitis with a 2-week

incubation

• Skin with widespread vesicular eruption

• Oral mucosa with short-lived vesicles that rupture forming shallow, defined ulcers

• Herpes zoster (shingles)

• Unilateral, dermatomal, grouped vesicular eruption of skin and/or oral mucosa

• Vesicles may coalesce prior to ulceration and crusting.

• Lesions are painful.

• Prodromal symptoms along affected dermatome may occur.

• Pain, paresthesia, burning, tingling

• Postherpetic pain may be severe.

Diagnosis

• Clinical appearance and symptoms

• Cytologic smear with cytopathic effect present (multinucleated giant cells)

• Viral culture or PCR examination of blister fluid or scraping from base of erosion

• Serologic evaluation of VZV antibody

• Biopsy with direct fluorescent examination using fluoresceinlabeled VZV antibody

Differential Diagnosis

• Primary herpes simplex/acute herpetic gingivostomatitis

• Recurrent intraoral herpes simplex

• Pemphigus vulgaris

• Mucous membrane (cicatricial) pemphigoid

Treatment

• Symptomatic management in primary infection

• Antiviral drugs (especially acyclovir) in immunocompromised patients or patients with extensive disease

• Systemic corticosteroids may be used to help control/prevent postherpetic neuralgia.

• Pain control to prevent “CNS imprinting”

Prognosis

• Generally good

• Recurrences more likely in immunosuppressed patients