Vesiculobullous Diseases

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Vesiculobullous Diseases

• Infectious (viral)
• Non-infectious (mucocutaneous)

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Vesiculobullous diseases infectious

• Herpes Simplex (HHV I (II)
• Primary
• Recurrent
• Varicella-zoster (HHV III)
• Primary
• Recurrent
• Coxsackie
• Herpangina
• Hand-foot-mouth disease
• Lymphonodular pharyngitis

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Viruses and oral disease
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Herpes Viruses

• Members of human herpesvirus family
• Type 1 (HSV-1 or HHV-1)
• Type 2 (HSV-2 or HHV-2)
• Varicella-zoster virus (VZV or HHV-3)
• Epstein-Barr virus (EBV or HHV-4)
• Cytomegalovirus (CMV or HHV-5)
• HHV-6 and HHV-7 two recently discovered viruses
• HHV-8

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Herpes Simplex Virus

• After initial infection, periods of latency
  reactivation
• HSV-1 spread predominantly through saliva or
  active perioral lesions
• HSV-2 spread mainly through sexual contact
• Antibodies to HSV-1 decrease chance of
  infection/severity of HSV-2

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Herpes Simplex Virus

• Primary infection - Initial exposure, often is
  asymptomatic
• Secondary or recurrent HSV-1 infection
  reactivation of virus, viral shedding. Symptoms
  affect epithelium via sensory ganglion. Virus
  easily spread through active lesions or
  asymptomatic viral shedding. Virus may spread to
  other sites in same host.

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Primary Herpes Simplex

• CLINICAL FEATURES
• Most infections occur during childhood and
  subclinically
• Few primary infections result in clinical disease
  
• Oral and perioral vesicles rupture, forming
  ulcers
• Intraoral lesions on any surface
• Systemic signs/symptoms (e.g., fever, malaise)
• Self-limited symptomatic care
• Immunocompromised have more severe disease
• TREATMENT
• Acyclovir and analogs may control virus
• Must use early to be effective

Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition.
8
Herpes Simplex Virus

• Acute herpetic gingivostomatitis
• Most common pattern of HSV-1 infection
• Usually occurs 6 months 5 years of age
• Pinhead vesicles, collapse to form small red
  lesions which develop ulceration
• Movable and attached oral mucosa can be affected
• Gingiva enlarged, painful, extremely erythematous
• Resolves 5-7 days (mild) or 2 weeks (severe)

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Herpes Simplex Virus
A. Herpes simplex induced vesicle. B.
Virus-infected multinucleated keratinocytes in
the wall of a vesicle.
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Pathogenesis of herpes simplex infection
Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier. 2002
11
Acute herpetic gingivostomatitis
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Acute herpetic gingivostomatitis
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Herpes Simplex Virus

• Herpes labialis (cold sore or fever blister)
• Most common site is vermilion border and adjacent
  skin of lips
• Prodromal symptoms 6-24 hours before lesion
  develops
• Small erythematous papules form clusters of
  fluid-filled vesicles
• Vesicles rupture within 2 days, healing occurs
  within 7-10 days

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Secondary Herpes Simplex

• ETIOLOGY
• Reactivation of latent herpes simplex virus type
  1
• Triggerssunlight, stress, immunosuppression
• Reactivation common frequency decreases with
  aging
• Prodromal symptomstingling and burning
• CLINICAL FEATURES
• Affects perioral skin, lips, gingiva, palate
• Self-limited
• TREATMENT
• Possible control with acyclovir and analogs
• Must administer early
• Systemic treatment much more effective than
  topical treatment

Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier.
15
Herpes labialis (cold sore or fever blister)
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Recurrent intraoral herpes
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Herpes Simplex Virus

• Herpetic whitlow (herpetic paronychia)
  infection of thumbs or fingers
• Herpes gladiatorum (scrumpox) - primary cutaneous
  herpetic infection in area of previous epithelial
  damage
• Eczema herpeticum (Kaposis varicelliform
  eruption) diffuse life-threatening HSV
  infection in patients with chronic skin diseases

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Herpes Zoster - Shingles

• Occurs after reactivation of VZV
• Predisposing factors include immunosuppression,
  radiation, malignancies, old age
• Presents as pain in epithelium innervated by
  affected sensory nerve (dermatome)
• Pain normally present 1-4 days before development
  of cutaneous or oral lesions. Lesions resolve
  within 2-3 weeks in healthy individuals

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Herpes Zoster - Shingles

• Zoster sine herpete recurrence without lesions
• Postherpetic neuralgia pain lasting longer than
  one month after episode
• Ramsay Hunt syndrome
• Cutaneous lesions of external auditory canal
  combined with involvement of facial, auditory
  nerves
• Causes facial paralysis, hearing loss, vertigo
• Oral lesions occur with trigeminal nerve
  involvement

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Varicella - Chickenpox

• Primary infection with VZV
• Herpes zoster after initial infection, virus
  establishes latency in dorsal spinal ganglia
• Symptoms include rash, malaise, fever
• Oral lesions common, may precede skin lesions
• Complications Reyes syndrome encephalitis

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Varicella-Zoster

• PRIMARY DISEASE (VARICELLA, CHICKENPOX)
• Self-limiting
• Common in children
• Vesicular eruption of trunk and head and neck
  occurring in crops
• Systemic signs/symptomsfever, malaise, other
• Symptomatic treatment
• SECONDARY DISEASE (ZOSTER, SHINGLES)
• Self-limiting
• Adults
• Rash, vesicles, ulcers unilateral along dermatome
  Postherpetic pain (15 of cases) can be severe
• Immunocompromised and lymphoma patients at risk
• Treated with acyclovir and analogs

Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
22
Varicella - Chickenpox
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Varicella - Chickenpox
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Herpes Zoster - Shingles

• Occurs after reactivation of VZV
• Predisposing factors include immunosuppression,
  radiation, malignancies, old age
• Presents as pain in epithelium innervated by
  affected sensory nerve (dermatome)
• Pain normally present 1-4 days before development
  of cutaneous or oral lesions. Lesions resolve
  within 2-3 weeks in healthy individuals

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Herpes Zoster - Shingles

• Zoster sine herpete recurrence without lesions
• Postherpetic neuralgia pain lasting longer than
  one month after episode
• Ramsay Hunt syndrome
• Cutaneous lesions of external auditory canal
  combined with involvement of facial, auditory
  nerves
• Causes facial paralysis, hearing loss, vertigo
• Oral lesions occur with trigeminal nerve
  involvement

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Herpes Zoster - Shingles
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Herpes Zoster - Shingles
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Herpes Zoster - Shingles
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Herpes Zoster - Shingles
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Enteroviruses

• Herpangina
• Most cases mild
• Sore throat, dysphagia, fever
• Small number of oral lesions develop in posterior
  areas of mouth (begin as red macules which form
  fragile vesicles that rapidly ulcerate)
• Systemic symptoms resolve in a few days,
  ulcerations take 7-10 days to heal

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Herpangina
Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
32
Herpangina
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Enteroviruses

• Hand-Foot-and-Mouth Disease
• Oral lesions almost always present
• Resemble oral lesions of herpangina but may be
  more numerous and are not confined to posterior
  area of mouth
• Most ulcerations resolve within one week

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Hand-Foot-and-Mouth Disease
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Hand-Foot-and-Mouth Disease

• A, B, C. Hand-foot-and-mouth disease.
  (Courtesy Dr. Steven K. Young.)

Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
36
Enteroviruses

• Acute Lymphonodular Pharyngitis
• Sore throat, fever, mild headache lasting 4-14
  days
• Yellow - dark pink nodules develop on soft palate
  or tonsillar pillars
• Nodules resolve within 10 days without
  vesiculation or ulceration

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Acute Lymphonodular Pharyngitis
38
Vesiculobullous diseases non-infectious

• Non-immunologic
• Epidermolysis bullosa
• Darier-White disease (keratosis follicularis)
• Immune-related
• Bullous lichen planus
• Erythema multiforme
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Autoimmune
• Pemphigus vulgaris
• Cicatricial pemphigoid
• Bullous pemphigoid
• Dermatitis herpetiformis
• Miscellaneous
• Allergic stomatitis

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Epidermolysis bullosa

• Epidermolysis bullosa is a general term that
  encompasses one acquired and several genetic
  varieties (dystrophic, junctional, simplex)
  characterized by the formation of blisters at
  sites of minor trauma.
• The several genetic types range from autosomal
  dominant to autosomal recessive in origin and are
  further distinguished by various clinical
  features, histopathology, and ultrastructure.
• In the hereditary forms, circulating antibodies
  are not evident. Rather, pathogenesis appears to
  be related to genetic defects in basal cells,
  hemidesmosomes, or anchoring connective tissue
  filaments, depending on the disease subtype.
• The acquired nonhereditary autoimmune form, known
  as epidermolysis acquisita, is unrelated to the
  other types and is often precipitated by exposure
  to specific drugs. In this type, IgG deposits are
  commonly found in sub-basement membrane tissue
  and type VII collagen antibodies located below
  the lamina densa of the basement membrane.

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Epidermolysis bullosa
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Epidermolysis bullosa
Complete separation of the epithelium from the
connective tissue is seen in this photomicrograph
of a tissue section obtained from a patient
affected by a junctional form of epidermolysis
bullosa. Neville. Oral and Maxillofacial
Pathology, 2nd Edition. Elsevier, 2002.
42
Darier's disease

• Uncommon genodermatosis with rather striking skin
  involvement and relatively subtle oral mucosal
  lesions.
• Inherited as an autosomal dominant trait, having
  a high degree of penetrance and variable
  expressivity.
• A lack of cohesion among the surface epithelial
  cells characterizes this disease, and mutation of
  a gene that encodes an intracellular calcium pump
  has been identified as the cause for abnormal
  desmosomal organization in the affected
  epithelial cells.
• Estimates of the prevalence of Darier's disease
  in northern European populations range from 1 in
  36,000 to 1 in 100,000.

Neville. Oral and Maxillofacial Pathology, 2nd
Edition. Elsevier, 2002.
43
Darier's disease

• Patients with Darier's disease have numerous
  erythematous, often pruritic, papules on the skin
  of the trunk and the scalp that develop during
  the second decade of life.
• An accumulation of keratin, producing a rough
  texture, may be seen in association with the
  lesions, and a foul odor may be present as a
  result of bacterial degradation of the keratin.
• The process generally becomes worse during the
  summer months, either because of sensitivity of
  some patients to ultraviolet light or because
  increased heat results in sweating, which induces
  more epithelial clefting.
• The palms and soles often exhibit pits and
  keratoses. The nails show longitudinal lines,
  ridges, or painful splits.

Neville. Oral and Maxillofacial Pathology, 2nd
Edition. Elsevier, 2002.
44
Darier's disease

• The onset occurs between the ages of 6 and 20
  years.
• The disease has a predilection for the skin, but
  13 of patients have oral lesions. Skin
  manifestations are characterized by small,
  skin-colored papular lesions symmetrically
  distributed over the face, trunk, and
  intertriginous areas. The papules eventually
  coalesce and feel greasy because of excessive
  keratin production.
• Fingernail changes may include fragility,
  splintering, and subungual keratosis. Nail
  changes are often helpful in establishing a
  diagnosis.
• The extent of the oral lesions may parallel the
  extent of skin involvement. Favored oral mucosal
  sites include the attached gingiva and hard
  palate. The lesions typically appear as small,
  whitish papules, producing an overall cobblestone
  appearance. Papules range from 2 to 3 mm in
  diameter and may become coalescent. Extension
  beyond the oral cavity into the oropharynx and
  pharynx may occur.

Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
45
Histopathology of Darier's disease
Microscopic examination of the shows a
dyskeratotic process characterized by a central
keratin plug that overlies epithelium exhibiting
a suprabasilar cleft (acantholysis). Not unique
to Darier's disease and may be seen in conditions
such as pemphigus vulgaris. The epithelial rete
ridges of the lesions appear narrow, elongated,
and test tube shaped. Close inspection of the
epithelium reveals varying numbers of two types
of dyskeratotic cells, called corps ronds (round
bodies) or grains (because they resemble cereal
grains).
Neville. Oral and Maxillofacial Pathology, 2nd
Edition. Elsevier, 2002.
46
Darier's disease
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Immunologic Mechanism/ Mediation of Skin Disease
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Epithelial attachment apparatus
Neville. Oral and Maxillofacial Pathology, 2nd
Edition. Elsevier, 2002.
49
Blisters
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Vesiculobullous diseases antigenic targets.
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Chronic Vesiculoulcerative Diseases
Neville. Oral and Maxillofacial Pathology, 2nd
Edition. Elsevier, 2002.
52
Immunofluorescence techniques
Neville. Oral and Maxillofacial Pathology, 2nd
Edition. Elsevier, 2002.
53
Patterns of Immunofluorescence
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Erythema Multiforme

• Self-limiting hypersensitivity response to
  infectious agents or drugs (by cytotoxic T cells).

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Erythema Multiforme Associated Conditions

• Infections HSV, Mycoplasma, histoplasmosis,
  typhoid, leprosy, coccidioidomycosis
• Drugs sulfonamides, penicillin, barbiturates,
  salicylates, hydantoins, antimalarials
• Cancers carcinomas lymphoma
• Autoimmune diseases dermatomyositis, SLE,
  polyarteritis nodosa

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Erythema Multiforme

• Sudden onset of macules, papules, vesicles,
  bullae target lesions
• Skin, mucous membranes, conjunctiva, urethra,
  anogenital region
• Usually self-limiting but Stevens-Johnson
  syndrome and toxic epidermal necrolysis variants
  can be severe and life-threatening

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Erythema multiforme

• Typical sloughing oral lesion Typical target
  skin lesion

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Erythema multiforme with genital lesion
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Erythema multiforme with conjunctivitis in
Stevens Johnson syndrome
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Erythema multiforme toxic epidermal necrolysis
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Lichen Planus

• Idiopathic, mucocutaneous, self-limiting in 1-2
  years
• Skin lesions are pruritic, purple, polygonal
  papules extensor of arms, flexor or legs,
  Wickham striae
• Post-inflammatory hyperpigmentation
• Oral lesions more common reticulated

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Lichen planus
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Oral Lichen planus
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Blistering (Vesiculobullous)Diseases

• Pemphigus
• Bullous pemphigoid
• Cicatricial pemphigoid (BMMP)
• Dermatitis herpetiformis

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Immunofluorescence laboratory methodology.
Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
66
Pemphigus

• Autoimmune attack on desmoglein 3, the
  intercellular cementing substance by an IgG
  autoantibody
• Most middle-aged progressive vegetans type can
  be fatal if untreated 1-5/1,000,000
• Vegetans, foliaceus and erythematosus subtypes
• Affects skin (scalp, face, groin, axilla, trunk)
  mucous membranes
• Suprabasal acantholytic blister
• Positive Nikolsky sign

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Pemphigus Vulgaris

• ETIOLOGY
• Autoimmune reaction to intercellular keratinocyte
  protein (desmoglein 3)
• Autoantibodies cause intraepithelial blisters
• CLINICAL FEATURES
• Affects skin and/or mucosa 50 or more of cases
  begin in the mouth ("first to show, last to go")
• Presents as ulcers preceded by vesicles or bullae
  
• Persistent and progressive
• TREATMENT
• Controlled with immunosuppressives
  (corticosteroids and azathioprine/cyclophosphamide
  )
• High mortality when untreated (dehydration,
  electrolyte imbalance, malnutrition, infection)

Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
68
Pemphigus vulgaris
69
(No Transcript)
70
Oral pemphigus vulgaris
A B. Oral pemphigus vulgaris showing
intraepithelial separation and Tzanck cells.
?Tzanck cells.
Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
71
Histopatholgy of pemphigus
72
Positive immunofluorescence (fish-net pattern) to
desmoglein 3 indicative of pemphigus
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Skin lesions in pemphigus vulgaris
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Oral lesions pemphigus vulgaris
Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
75
Oral lesions pemphigus vulgaris
76
Bullous Pemphigoid

• Autoimmune attack of the basal lamina zone
  hemidesmosome
• Tense bullae thighs, flexor forearms, axillae,
  groin, lower abdomen oral involvement 8-39
• Older adults 10/1,000,000 positive Nikolsky
  sign tends to be limited

77
Bullous pemphigoid
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Bullous pemphigoid
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Cicatricial Pemphigoid(Mucous Membrane
Pemphigoid)

• ETIOLOGY
• Autoimmune reaction to basement membrane proteins
  (laminin 5 and BP180)
• CLINICAL FEATURES
• Oral mucosa (gingiva often only site) and
  conjunctiva skin rarely affected
• Autoantibodies cause subepithelial blisters
• Present as ulcers/redness in older adults (over
  50)
• Persistent, uncomfortable to painful
• TREATMENT
• Controlled with corticosteroids sometimes
  resistant to systemic therapy topical agents
  useful
• Significant morbidity if untreated, including
  pain and scarring, especially of eye

80
Cicatricial Pemphigoid

• Autoimmune attack on BLZ more common than
  pemphigus
• Oral lesion are most common may have
  conjuctival, nasal, esophageal, laryngeal,
  vaginal lesions
• Also known as benign mucous membrane pemphigoid
• 21 females age 50-60 Nikolsky sign tends to
  be progressive

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Oral lesions of cicatricial pemphigoid
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Oral lesions of cicatricial pemphigoid
Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
83
Ocular lesions in cicatricial pemphigoid
84
Symblepheron (chronic ocular pemphigoid)
Regezi. Oral Pathology Clinical Pathologic
Correlations, 4th Edition. Elsevier, 2002.
85
Bullous or cicatricial pemphigoid --
subepithelial blister
86
Cicatricial (mucous membrane) pemphigoid
basement membrane immunofluorescent staining.
Courtesy Dr. Troy E. Daniels. Regezi. Oral
Pathology Clinical Pathologic Correlations, 4th
Edition. Elsevier, 2002.
87
Positive immunofluorescence along basal lamina
(candy ribbion pattern) indicative of bullous
pemphigoid
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Comparision of Pemphigus Pemphigoid
89
Dermatitis Herpetiformis

• Rare autoimmune (IgA-autoantibodies localized in
  tips of dermal papillae)
• Urticaria with closely grouped vesicles pruritic
  rash elbows, knees, upper back, buttocks
• Age 20-30 celiac disease
• Responds to gluten-free diet

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Dermatitis herpetiformis
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Dermatitis/stomatitis herpetiformis
Skin lesions
Intraoral lesions