Senin, 28 November 2011

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

Epidermolysis Bullosa

• 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.

• 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

• 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

• Widely variable depending on subtype

Erythema Multiforme

• 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.

• 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

• 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.

• Generally excellent
• Recurrences common


Hand-Foot-and-Mouth Disease

• 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

• 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

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

• Excellent
• Lifelong immunity, but it is strain specific


• 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

• 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

• Soft diet
• Hydration
• Antipyretics
• Chlorhexidine rinses
• Compounded mouth rinses

• Excellent

Herpetic Stomatitis: Primary

• 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

• 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)

• 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

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


• 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)

• 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

• Topical antibiotics (mupirocin, clindamycin)
• Systemic antibiotics

• Excellent
• Rarely, poststreptococcal glomerulonephritis may develop.

Mucous Membrane Pemphigoid

• 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

• Biopsy
• Direct immunofluorescent examination

Differential Diagnosis
• Pemphigus vulgaris
• Erythema multiforme
• Erosive lichen planus
• Lupus erythematosus
• Epidermolysis bullosa acquisita

• Topical corticosteroids
• Systemic prednisone, azathioprine, or cyclophosphamide
• Tetracycline/niacinamide
• Dapsone
• See “Therapeutics” section for details.

• 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

• 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

• 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

• Identification of concurrent malignancy
• Immunosuppressive therapy

• Good with excision of benign neoplasms
• Grave, usually fatal, with malignancies
• Management is very challenging.

Pemphigus Vulgaris

• 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

• Clinical appearance
• Mucosal manifestations
• Direct/indirect immunofluorescent studies

Differential Diagnosis
• Mucous membrane (cicatricial) pemphigoid
• Erythema multiforme
• Erosive lichen planus
• Drug reaction
• Paraneoplastic pemphigus

• Systemic immunosuppression
• Prednisone, azathioprine, mycophenolate mofetil, cyclophosphamide
• Plasmapheresis plus immunosuppression
• IVIg for some recalcitrant cases
• See “Therapeutics” section for details.

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

Recurrent Herpetic Stomatitis: Secondary

• 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).

• 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

• 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.

• Excellent
• Healing without scarring within 10 to 14 days
• Protracted healing in HIV-positive patients

Stevens-Johnson Syndrome

 • 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

• 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

• 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

• Good; self-limiting usually
• Recurrences not uncommon

Varicella and Herpes Zoster

• 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
• 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.

• 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

• 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”

• Generally good
• Recurrences more likely in immunosuppressed patients