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PATHOLOGY OF THE SKIN
1. Inflammatory skin diseases and
bullous skin disorders
Máirín E. McMenamin MB MRCPI FRCPath Dip (Dermatopathol) RCPath
St. James’s Hospital and University of Dublin, Trinity College
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Skin is the largest organ in the body and acts
as a cornified envelope
Skin has many properties:
ECS
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Glomus body: modified perivascular smooth muscle cells,
involved in temperature regulation
Regional variability in skin
Skin of forearm
Skin of nose – numerous
sebaceous glands
ECS
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Langerhans’ cell in mid epidermis
Langerhans’ cells stain positively
for S100 protein and CD1a
They are increased in number
in contact allergic dermatitis
Electron microscopy:
Langerhan’s cells
show intracytoplasmic
rod and racket
shaped cytoplasmic
inclusions
OVERVIEW OF SKIN PATHOLOGY
• Congenital skin diseases
• Papulosquamous diseases
(scaly skin diseases)
• Vesiculobullous diseases
(blistering skin diseases)
• Infections
– Bacteria (S.aureus, impetigo, staphylococcal scalded skin
syndrome, Strep. cellulitis)
– Mycobacteria (e.g. T.B., leprosy)
– Fungus (e.g. dermatophytosis and dermatomycosis)
– Virus (e.g. Herpes simplex, molluscum contagiosum, orf)
– Spirochaetes (e.g. syphilis, borrelia)
– Protozoa (e.g. amoebiasis, leishmaniasis, toxoplasmosis)
– Helminths (schistosomiasis, larva migrans)
– Arthropod – induced diseases (demodex, scabies,
bedbugs, tick bites)
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• Skin diseases can be acute self limited (e.g.
acute folliculitis), recurrent (herpes simplex
infection), chronic (psoriasis)
• Some conditions can be life threatening
e.g. staphylococcal scalded skin syndrome,
toxic epidermal necrolysis, severe
pemphigus
SELECTED GENODERMATOSES
• Urticaria pigmentosa (some cases have somatic mutations of ckit)
– Tan macules, accumulation of mast cells in dermis
– Positive Darier sign (urtication (wheal) when skin is rubbed)
– Rarely systemic involvement e.g. bone marrow
• Ichthyosis (disorder of keratinization)
– Many variants of variable severity
– Ichthyosis vulgaris due to mutations in filaggrin gene
• Acantholytic disorders (abnormal calcium channel proteins)
– Usually autosomal dominant
• Hailey-Hailey disease (Greasy confluent papules in axillae)
• Darier disease (Greasy confluent papules in seborrhoeic areas)
• Xeroderma pigmentosa (inability to repair UV- induced DNA breaks)
– Autosomal recessive
• Severe actinic (sun-induced) damage
• Squamous cell carcinomas at an early age
• Epidermolysis bullosa
• Many variants of variable severity, autosomal dominant or recessive
• Blistering, contractures, mitten deformities, squamous cell carcinomas
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Urticaria pigmentosa
Accumulation of mast cells in the dermis
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Dermatographism: urtication (wheals)
Positive Darier sign (urtication (wheal) when skin is rubbed
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Ichthyosis (sex-linked variant)
Disfiguring scaling of skin
Lamellar ichthyosis
Scaling and erythema
Ichthyosis vulgaris
Lamellar ichthyosis
Increase in keratin in stratum corneum
Congenital ichthyosiform erythroderma
Intense erythema and fine scaling
Hyperkeratosis and vacuolation
of epidermis
Congenital ichthyosiform erythroderma
Genetic bullous diseases
• Abnormalities in various proteins in basement
membrane region
– Dystrophic epidermolysis bullosa
• Mutations in collagen VII
– Junctional epidermolysis bullosa
• Mutations in laminin 5
• Autoimmune bullous diseases can show antibodies
to similar proteins e.g. bullous pemphigoid and
bullous SLE
DERMATITIS
Inflammation of the skin
Many aetiological factors:
• Exogenous sensitizing agents
– (contact allergic dermatitis and contact irritant
dermatitis)
• Proteins (e.g. biological detergents)
• Haptens (e.g. nickel)
• Endogenous agents
• Drugs (e.g. trimethoprim)
• Atopic individuals (excess production of Ig E)
• Atopic dermatitis (eczema)
– mutations in filaggrin gene
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DERMATITIS
CLINICAL FEATURES
• Acute dermatitis
– Sore, red, weeping skin +/- pruritic (itchy)
• Chronic dermatitis
– Indurated lichenified skin (thickened skin)
Anatomic distribution of dermatitis can be helpful in
elucidating cause
e.g. contact allergic dermatitis:
On exposed skin of arms (poison ivy)
Under watch (nickel)
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Acute dermatitis
Spongiosis with
epidermal vesicles
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With continuation of the dermatitis the skin shows features of
subacute spongiotic dermatitis with elongated rete ridges and
surface scale crust
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DERMATOPATHIC LYMPHADENOPATHY
• Reactive enlargement of lymph nodes draining an
area in which there is an inflammatory skin
condition
• Histologically the node shows sinus histiocytosis
with numerous Langerhans’ cells and
phagocytosed melanin pigment and lipid
• May be misinterpreted as lymphoma
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NON-INFECTIOUS VESICULOBULLOUS SKIN DISEASE
• Pemphigus
– P. vulgaris/ p. foliaceus/ paraneoplastic pemphigus
• Pemphigoid
– Bullous pemphigoid
– Herpes gestationis (bullous pemphigoid in pregnancy)
– Mucous membrane pemphigoid (cicatricial pemphigoid)
(scarring, can cause blindness)
• Dermatitis herpetiformis
– association with coeliac disease
• Acquired epidermolyis bullosa (antibodies to collagen VII)
• Erythema multiforme
– Frequently related to exposure to a drug or virus (herpes simplex)
– Clinical spectrum with Stevens-Johnson syndrome and toxic
epidermal necrolysis
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Basement membrane region of
normal epidermis
Electron microscopy
Anchoring fibrils:
collagen VII
Cartoon of basement membrane proteins
Anchoring fibrils
Lamina lucida
Hemidesmosome
Lamina densa
NON-INFECTIOUS VESICULOBULLOUS SKIN DISEASE
• For accurate diagnosis the clinical and histological features
need to be correlated and frequently supportive
immunological studies are needed for accurate diagnosis
• Histological study:
– Performed on lesional skin (bulla)
• Immunological studies:
– Direct immunofluorescence
• Performed on perilesional skin (skin adjacent to a
bulla)
– Indirect immunofluoescence: patient’s serum tested
against a substrate such as monkey oesophagus
– Other serological tests such as ELISA used for
quantitation of autoantibodies in patient’s blood
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PEMPHIGUS VULGARIS
• Uncommon blistering disease affecting scalp, face +/- mucous
membranes
• M=F, 30-60 y
• Acantholysis in apparently normal skin may be clinically
demonstrated by the Nikolsky sign:
– Slippage of superficial layers of normal skin on application of a
shearing force
• Generally chronic relapsing course
• If extensive loss of fluid, protein, electrolytes +/- infection may
prove fatal
• Histopathology: Separation (acantholysis) of epidermal cells leaves
basal cells attached to basement membrane by hemi-desmosomes
– Characteristic “tombstone” appearance on biopsy
• Circulating autoantibodies to desmogleins (components of
desmosomes)
• Direct immunofluorescence: intercellular deposition of IgG and C3
• Paraneoplastic pemphigus can occur in malignancy e.g. lung cancer
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Pemphigus vulgaris: flaccid blisters and erosions
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Pemphigus vulgaris
Direct immunofluorescence:
Intercellular deposition of IgG and C3
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BULLOUS PEMPHIGOID
•
•
•
•
Large tense bullae on thighs, flexures and lower abdomen
Bullae do not rupture easily
M=F, elderly
Histology:
– Eosinophil infiltration in dermis
– Subepidermal bulla (dissolution of lamina lucida of
basement membrane and separation of entire epidermis)
• Direct immunofluorescence:
– Linear deposition of IgG and C3 along basement membrane
• May have detectable levels of anti-basement membrane
antibodies:anti bullous pemphigoid antigens 1 and 2
(BPAG1 and BPAG2)
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Bullous pemphigoid: tense blisters on extremities
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Basement membrane region of
normal epidermis
Electron microscopy
Anchoring fibrils:
collagen VII
Cartoon of basement membrane proteins
Anchoring fibrils
Lamina lucida
Lamina lucida
Hemidesmosome
Lamina densa
Lamina densa
Bullous pemophigoid
Linear deposition of IgG and C3 along
dermo-epidermal junction
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DERMATITIS HERPETIFORMIS
• Grouped intensely itchy vesicles over joints, upper back
and buttocks
• M > F, 20-40y
• Histology:
– Neutrophilic microabscesses in papillary dermis
– Separation of epidermis at papillary tips in a festooned
pattern, coalescing to form bullae
• Direct immunofluorescence:
– Granular deposits of IgA in dermal papillae (on anchoring
filaments)
• Strong association with coeliac disease (gluten sensitive
enteropathy)
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Dermatitis herpetiformis
Granular deposition of IgA along dermo-epidermal junction
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ERYTHEMA MULTIFORME
• Cytotoxic skin reaction, commonly initiated by infections
(e.g. herpes viral infection) or drugs (e.g. sulphonamides)
• M = F, any age
• Typically gives rise to “targetoid lesions” but may appear
as macules, papules, vesicles or bullae
• Extremities affected in most cases, but may be widespread,
(especially in children) with mucosal involvement
(Stevens-Johnson syndrome)
• Histologic features:
– Lymphocytes attack basal layer causing epidermal necrosis and
vesiculation
• Direct immunofluorescence: unhelpful
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Erythema multiforme: targetoid lesions on hands
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PAPULOSQUAMOUS SKIN DISEASES
• Psoriasis
• Cutaneous lupus erythematosus
– Discoid lupus, subacute lupus, bullous lupus erythematosus
• Lichen planus
• Pityriasis rubra pilaris
• Porokeratosis
• Graft-versus-host disease
– Seen especially after allogeneic transplantation (many organs can
be affected and patients can present with rash / GI symptoms /
elevated liver function tests)
PSORIASIS
• Disorder of epidermal proliferation, affecting 2% of population
• M = F, mean age of onset 25-30 y
• Typically affects elbows, knees, scalp, natal cleft chronically but can
be acute and generalized (erythroderma) and can be pustular
• Mucous membranes rarely affected e.g. tongue
• Guttate variant typically affects children, commonly after
streptococcal infection (small drop-sized plaques)
• Clinical features:
– Silvery scaly lesions on an erythematous background with pinpoint
bleeding when scraped or scale is removed (Auspitz sign)
• Histological features:
– Elongated rete ridges, club-shaped papillae, suprapapillary thinning, loss
of granular cell layer and neutrophils in epidermis and stratum corneum
(spongiform pustules of Kojog and Munro microabscesses)
• Turnover of epidermis is increased
– (4 days from basal cell layer to shedding, normally takes several weeks)
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Chronic plaque psoriasis
affecting arm and trunk
Pustular psoriasis: sterile pustules
on an erythematous base
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Psoriasis showing elongated
rete ridges
Neutrophils in epidermis
(spongiform pustule)
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PSORIASIS
• Aetiology unknown
– Probably related to damage to the stratum corneum in certain HLA
types, unmasking antigens against which antibodies form
– Complement activation attracts neutrophils which unmask further
antigens
– Epidermal growth factor (EGF) released by damaged keratinocytes
causes persistent proliferation
• Other important points about psoriasis
– Pustular variant involves palms and soles
– Nail changes common - nail pitting in 30%, onycholysis
– Associated with arthritis - several forms
• (asymmetrical arthritis hands and feet, symmetrical seronegative
[rheumatoid arthritis-like], arthritis mutilans, ankylosing
spondylitis)
– Exacerbated by certain drugs (e.g. lithium, beta blockers)
– HIV seroconversion can be accompanied by acute psoriasis
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Nail pitting in psoriasis
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Porokeratosis
Several clinical variants all characterised by
cornoid lamella (tier of parakeratosis)
LUPUS ERYTHEMATOSUS
• Chronic discoid lupus erythematosus (DLE) is
characterized by scaling rash affecting central face
(cheeks, nose) can have butterfly distribution
• DLE can cause scarring alopecia
• Frequently exacerbated by ultraviolet light
• DLE rarely progresses to systemic lupus
erythematosus (SLE)
• Histology:
– Autoimmune destruction of basal cell layer
– Vacuolar interface damage of basal keratinocytes
• Direct immunofluorescence:
– Granular deposition of IgG and C3 along basement
membrane (“lupus band”)
• Variable detection of anti-nuclear antibodies (ANA) in
serum in DLE, high titre suggests SLE
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Discoid lupus erythematosus
vacuolar interface damage to basal cell layer
Apoptotic
keratinocytes
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LICHEN PLANUS
• Pruritic polygonal purple papules on wrists, ankles and
elbows, papules can coalesce to form plaques
• Often involves mucous membranes with a white reticulate
(net-like) pattern
• Self-limited condition
• Aetiology unknown (probably autoimmune)
– Sometimes associated with drugs (e.g naproxen)
• Histologic features:
– Characterized by band-like T cell infiltrate at the
dermo-epidermoid junction (lichenoid reaction) with
damage (wipe-out) of basal cells
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LICHEN PLANUS
Skin infections
• Bacterial: (especially Staph aureus, Streptococcal species)
cellulitis, folliculitis, abscesses, impetigo, Staphylococcal
scalded skin syndrome: superficial exfoliation due to toxin
• Fungal: ringworm (dermatophytosis), deep fungal
infections (dermatomycoses) especially in
immunosuppression
• Mycobacterial: mycobacterium tuberculosis,
ermycobacterium marinum (fish-tank granuloma)
mycobacterium leprae (leprosy)
– Granulomatous inflammation, mycobacteria can be seen on Ziehl
Neelson or modified Ziehl Neelson stains
• Viruses e.g. verrucae (HPV), herpes simplex, varicella
zoster, molluscum contagiosum (pox virus)
Herpes viral infection
Bulla with multinucleate epidermal cells
showing herpetic nuclear inclusions
(herpes simplex, varicella zoster)
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Molluscum contagiosum (Pox virus)
Viral inclusions
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Verruca vulgaris (wart) HPV viral infection
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Dermatopathology – some important
facts for the clinician
• Histological features are not always specific
• Careful correlation is needed with clinical features and
other studies, where appropriate (special histological
stains, immunology, microbiology, genetics)
• Appropriate clinical information on request forms and
timely delivery to lab where appropriate, direct
communication with pathologist / dermatologist can help
prior to biopsy
• Responsibility in choice of site of biopsy can be very
important and is informed by potential diagnosis (e.g. edge
of intact bulla not ulcerated bulla, get cornoid lamella in
porokeratosis)