Diseases of SKIN

Vesiculobullous Lesions

Pemphigus

Dr. Anthony George

Dept. of Oral & Maxillofacial Pathology and Oral Microbiology
 Pemphigus
Variants / types of pemphigus
1. Pemphigus vulgaris.
2. Paraneoplastic pemphigus.
3. Familial benign pemphigus (Hailey-Hailey
disease).
4. Pemphigus vegetans.
5. Pemphigus foliaceus (Brazilian wildfire).
6. Pemphigus erythematous.
7. Pemphigus herpetiformis.
8. Drug-induced pemphigus.
9. IgA pemphigus.
10.Endemic pemphigus (fogo selvagem).
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Pemphigus Vulgaris
 Pemphigus Vulgaris
Vulgaris – Latin word meaning „common‟.
(Lupus vulgaris – Tuberculosis of skin).

Pemphigus Vulgaris is mucocutaneous blistering

disease, caused by circulating autoantibodies,
directed against keratinocyte transmembrane
proteins, resulting in intraepithelial split.

Of all variants only Pemphigus Vulgaris occurs in

oral cavity.
Oral lesions may appear first (before skin lesions)
Last to resolve after initiation of treatment.
Patho-physiology (Etiology)
 Vesiculobullous Lesions
For unknown reasons autoantibodies are directed
against cell junctions that hold epithelial cells
together, causing damage to host tissue, resulting in
clinical appearance of vesiculo-bullous lesions.

Auto-anti-bodies – inappropriate production of

antibodies against normal constituents (self antigens) of
human body.

Adhesive Cell Junctions

Cell to cell adhesive junction – desmosomes.
Cell to matrix adhesive junction – hemidesmosomes.

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 Unknown reason.
Individuals with certain human lymphocyte antigen (HLA) are more prone.

IgG (G1 & G4) & C3 autoantibodies produced

against transmembrane adhesive protein of
desmosomal cell junction
E-cadherin protein – desmoglein 1 & 3.
» Desmoglein 1 is expressed more in upper layers of skin.
» Desmoglein 3 is expressed more in supra basal cell layer of
oral mucosa.

Intraepithelial supra basal cleft (blister) containing

clear fluid develop due to lack of cell adhesion.
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Clinical Features
 Pemphigus Vulgaris: Clinical Features
Epidemiology
Rare skin disease (1 in 1 million).

Age: 50-60 yrs (30-50 yrs in Indian population).

Gender: No gender predilection.
Race: More common in Jews, south Asians.

Site:
In oral cavity commonly seen in – palate, labial & buccal
mucosa, tongue, gingiva.

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 Pemphigus Vulgaris: Clinical Features
Skin Lesions
Rapid appearance of flaccid vesicles and bulla
covering large areas of skin.
Few mm to several cm in size.

Initially contain thin watery clear fluid.

Later become purulent due to pus formation – dead
cells.

Bulla rupture easily due to thin roof of bulla to form

raw eroded painful erythematous areas.

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 Pemphigus

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 Pemphigus Vulgaris: Clinical Features
Oral Manifestations
Oral lesions may appear first in 50% of cases.
May appear 1 yr earlier to skin lesions.

1. Intact bulla are rare in oral cavity as roof is thin &

friable – rupture easily during mastication.
Bulla rupture to form ill-defined, irregularly
shaped, superficial erosions or painful ulcers.
Patient unable to eat and drink due to painful ulcers
that are slow to heal.

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 Pemphigus Vulgaris: Clinical Features
Haphazardly distributed map-like painful ulcerated
lesions of buccal mucosa and palate.
Mucosa appear to peal away from surface.
Upper layers of mucosa can be lifted up with dental
probe.
Lesions may involve larynx leading to hoarseness of
voice.

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 Pemphigus Vulgaris: Clinical Features
2. Desquamative gingivitis.
Painful eroded erythematous
marginal and interdental gingiva.
No plaque or calculus deposits.
3. Cerebriform tongue.
Dorsum of tongue have painful
ulcers forming deep sulcus and
grooves.

Painful eroded and ulcerated

lesions on ventral surface and tip of
tongue.
Palatal mucosa may be involved.
 Pemphigus Vulgaris: Clinical Features
4. Nikolsky’s sign is positive.
Diagnostic clinical skin test for vesiculobullous
lesions.

Application of oblique lateral pressure on

unaffected skin produce clear fluid filled blister.
Lateral pressure cause disruption of desmosomal cell
junctions resulting in split in epithelium.

In oral cavity air blown from 3-way syringe of dental

unit on gingiva will produce clear fluid filled blister.

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Histopathological Investigation
 Pemphigus Vulgaris
Special care during BIOPSY
Biopsy should be taken from peri-lesional tissue.
Obtained peri-lesional tissue is incubated in salt solution
to create blister – salt split technique
Should be submitted in Michel’s solution (fixative) or
frozen in liquid nitrogen to prevent pealing away of
epithelium.
10% formalin to be avoided as fixative.
Diagnosis cannot be made if ulcerated mucosa
without epithelium is submitted.
Epithelium should be present to identify level of split for
diagnosis.
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 Pemphigus Vulgaris: Histopathology
1. Supra basal intraepithelial cleft (separation) with
lifting of superficial epithelium.
Loss of desmosomal cell junctions.
2. Basal cells appear as ‘row of tombstones’ in floor
of bulla.
3. Stratum spinosum show acantholysis –
‘dilapidated brick wall’ appearance.
4. Tzanck Cells = clumps of loose round
degenerating swollen epithelial cells with hyper-
chromatic nucleus lying free in vesicular space.

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 Pemphigus Vulgaris: Histopathology

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Cytological Investigation
 Pemphigus Vulgaris
Tzanck Test
Cytological diagnostic test for pemphigus.
Un-ruptured intact bulla is pierced with sterile fine
needle and fluid content is obtained.
Cytological smear is prepared on clean glass slide.
Smear is stained with PAP stain.
Studied under microscope for Tzanck Cells.
Clumps of round swollen epithelial cells with hyper-
chromatic nucleus.
Special Investigations
Immuno Fluorescence
 Immuno Fluorescence
Special diagnostic technique to identify specific
antibodies produced.
Fluorescence: property of some chemical
substances which when illuminated by light of certain
wavelength (UV light) will re-emit light of longer
wavelength.
Studied under Fluorescent Microscope.

Two Variants of Immunofluorescent Technique

1. Direct immunofluorescence (DIF).
2. Indirect immunofluorescence (IIF).
Antibodies directed against
human immunoglobulin's to
be studied are created by
inoculating them into goat.

Harvested goat antihuman

antibody are tagged or
conjugated with
fluorochromes.
Antibodies directed against
human immunoglobulin's to
be studied are created by
inoculating them into goat.

Harvested goat antihuman

antibody are tagged or
conjugated with
fluorochromes.
 Pemphigus vulgaris
Direct immunofluorescence microscopy (DIF)
Immunoreactants deposited throughout epithelium –
‘chicken wire’ or ‘fish net’ appearance.
Demonstrates IgG (G4 & G1) in intercellular spaces of
epithelial cells in 90-100% of patients.
C3, IgM, IgA deposition seen less commonly –
commonly found in clinically normal adjacent
epithelium.

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 Pemphigus vulgaris
Indirect immunofluorescence microscopy (IIF)
Circulating IgG autoantibodies to squamous
intracellular substance seen in 80-90% of cases.
C3, IgM, IgA may also show positivity.
Titers of circulating autoantibodies can be measured
– helps in treatment planning.

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Treatment
 Pemphigus vulgaris
Initial high dose of systemic corticosteroids
followed by low dose if required.
Long term therapy avoided due to side effects.
Immuno-suppression, glaucoma, osteoporosis,
hyperglycemia, hypertension, peptic ulcer, weight gain.
Prednisone – 5 mg OD for 2 weeks.
Dose to be tapered before drug stoppage.
Antiseptic and analgesic dressing to relive pain.
Topical corticosteroids for prevention of relapse.
15 g for 2-4 weeks.
Combined with topical candidal cream to avoid
candida albicans infection (candidiasis).
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 Pemphigus vulgaris
Immuno suppressive drugs
Cyclophosphamide.
Azathioprine.
Methotrexate.
Combination of systemic corticosteroids & immuno
suppressive drugs are presently used.
Alternate days of prednisone & methotrexate.

Immunophoresis – IV administration of 8-methoxy

psoralen, followed by exposure of peripheral blood
to UV radiation.

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 Paraneoplastic Pemphigus
(Neoplasia induced pemphigus)

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 Paraneoplastic Pemphigus
Rare autoimmune mucocutaneous vesiculobullous
disorder that affects patients with underlying
neoplasm, especially
Non Hodgkin Lymphoma.
Chronic Lymphocytic Leukemia.
Poorly Differentiated Sarcomas.

Mucocutaneous lesions may develop even before

malignancy is diagnosed.
Characterized by intra-epithelial and sub-epithelial
blister formation.

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Pathophyiology
 Paraneoplastic Pemphigus
Lymphocytes produce cytokines and interleukin (IL) 6 due to
host response to underlying neoplasm evoking auto-immune
response.

Abnormal antibody formed cause cross reactivity with

desmosomal junction and basement membrane.
 Desmoglein 1 & 3.
 Desmoplakin 1 & 2.
Major bullous pemphigoid antigen 1 (BP230).
Envoplakin.
Periplakin.

Intra-epithelial & sub-epithelial blister formation.

Clinical Features
 Paraneoplastic Pemphigus
Age: 60-70 yrs.
Gender: No gender predilection.
History of underlying malignant neoplasm.

Multiple polymorphous papular and pruritic

mucocutaneous lesions of sudden onset.
May resemble Lichen Planus.

Palmar and plantar bulla.

Rarely seen in pemphigus or other vesiculobullous
lesions.
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 Paraneoplastic Pemphigus
Multiple erythematous diffuse irregular painful
ulceration of any oral mucosal surface.
Mucosal lesion may appear earlier to skin lesions.

Hemorrhagic crusting of lips.

Similar to erythema multiforme.

70% show conjunctivitis and ocular involvement that

heal with scaring.
Vaginal & respiratory mucosa maybe involved.
Epistaxis maybe seen if nasal mucosa affected.
 Paraneoplastic Pemphigus

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Histopathology
 Paraneoplastic Pemphigus
Intraepithelial and subepithelial clefting (split).
Acantholysis of supra basal layer.
Dyskeratosis
Deposition of keratin in stratum spinosum.
Keratin seen within bulla – diagnostic feature for
paraneoplastic pemphigus.
Spongiosis – „basket weave‟ appearance.
Vesicular nucleus.

Connective tissue show lymphocytic infiltrate and

peri-vascular inflammation.
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 Paraneoplastic Pemphigus

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 Special Investigations:
Immunofluorescence studies
 Paraneoplastic Pemphigus
Direct immunofluorescence microscopy (DIF)
Weakly positive for IgG & C3 in intraepithelial region.
Linear granular deposition of immunoreactants at
basement membrane.

Indirect immunofluorescence microscopy (IIF)

Specific pattern of antibody localization to intercellular
spaces of rat urinary bladder mucosa.
Desmoglein 1 & 3.
Desmoplakin 1 & 2.
BP 230.
Envoplakin & Periplakin.
Treatment
 Paraneoplastic Pemphigus
Surgical removal of malignant tumor usually
cause regression of vesiculobullous lesions.

Systemic corticosteroids in combination with

immunosuppressive drugs.

Immunophoresis – IV administration of 8-methoxy

psoralen followed by exposure of peripheral blood to
UV radiation.

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Prognosis
 Paraneoplastic Pemphigus
Skin lesions react faster to medication than oral
lesions – “oral lesions are 1st to show & last to go”.

Poor prognosis with 90% mortality.

Complication: dehydration, electrolyte imbalance,
malnutrition, secondary infections.
Complication of immunosuppressive therapy.
Progression of malignant disease.

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 Histopathological Terminology
Hyperkeratosis – increased thickness of stratum corneum.
Acanthosis – increased thickness of stratum spinosum.
Acantholysis – destruction of desmosomal cell junctions
and separation of epithelial cells from one another.
Spongiosis – intercellular edema.
Cytolysis – destruction of cells (viral infections).

Hyperkeratosis & Acanthosis Acantholysis & Spongiosis Cytolysis