1. Copyright M. McMenamin

2. 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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3. Skin is the largest organ in the body and acts as a cornified envelope Skin has many properties:

4. ECS
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6. Glomus body: modified perivascular smooth muscle cells, involved in temperature regulation

7. Regional variability in skin
Skin of nose – numerous sebaceous glands
Skin of forearm
Fig Skin from forearm showing a fairly thin epidermis. Compare the thickness of the dermis with that from the back. Two eccrine sweat glands are present.

8. ECS
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9. 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

10. 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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11. Skin diseases can be acute self limited (e. g
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

12. 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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13. Accumulation of mast cells in the dermis
Urticaria pigmentosa
Accumulation of mast cells in the dermis
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14. Dermatographism: urtication (wheals)
Positive Darier sign (urtication (wheal) when skin is rubbed
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15. Ichthyosis (sex-linked variant) Disfiguring scaling of skin

16. Lamellar ichthyosis Scaling and erythema

17. Ichthyosis vulgaris Lamellar ichthyosis
Increase in keratin in stratum corneum

18. Congenital ichthyosiform erythroderma Intense erythema and fine scaling
Hyperkeratosis and vacuolation of epidermis

19. Congenital ichthyosiform erythroderma

22. 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

23. Inflammation of the skin
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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24. 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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25. Acute dermatitis Spongiosis with epidermal vesicles
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26. 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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27. 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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28. 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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29. Basement membrane region of normal epidermis
Cartoon of basement membrane proteins
Electron microscopy
Anchoring fibrils: collagen VII
Anchoring fibrils
Lamina lucida
Lamina densa
Hemidesmosome
Fig Basement membrane region of normal epidermis: electron micrograph showing epidermodermal junction. Note the conspicuous basal keratinocyte hemidesmosomes, the lamina lucida and lamina densa. (D, dermis; K, keratinocyte; N, nucleus; T, tonofilament; arrows, anchoring fibrils.)

30. 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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31. PEMPHIGUS VULGARIS
Uncommon blistering disease affecting scalp, face +/- mucous membranes
M=F, 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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32. Pemphigus vulgaris: flaccid blisters and erosions
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33. Direct immunofluorescence: Intercellular deposition of IgG and C3
Pemphigus vulgaris
Direct immunofluorescence:
Intercellular deposition of IgG and C3
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34. 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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35. Bullous pemphigoid: tense blisters on extremities
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36. Basement membrane region of normal epidermis
Cartoon of basement membrane proteins
Electron microscopy
Anchoring fibrils: collagen VII
Anchoring fibrils
Lamina lucida
Lamina lucida
Lamina densa
Hemidesmosome
Fig Basement membrane region of normal epidermis: electron micrograph showing epidermodermal junction. Note the conspicuous basal keratinocyte hemidesmosomes, the lamina lucida and lamina densa. (D, dermis; K, keratinocyte; N, nucleus; T, tonofilament; arrows, anchoring fibrils.)
Lamina densa

37. Bullous pemophigoid Linear deposition of IgG and C3 along
dermo-epidermal junction
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38. 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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39. Dermatitis herpetiformis
Granular deposition of IgA along dermo-epidermal junction
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40. 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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41. Erythema multiforme: targetoid lesions on hands
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42. 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)

43. PSORIASIS
Disorder of epidermal proliferation, affecting 2% of population
M = F, mean age of onset 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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44. Chronic plaque psoriasis affecting arm and trunk
Pustular psoriasis: sterile pustules on an erythematous base
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45. Psoriasis showing elongated rete ridges
Neutrophils in epidermis (spongiform pustule)
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46. PSORIASIS Aetiology unknown Other important points about psoriasis
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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47. Nail pitting in psoriasis
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48. Porokeratosis Several clinical variants all characterised by cornoid lamella (tier of parakeratosis)

49. 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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50. Discoid lupus erythematosus
vacuolar interface damage to basal cell layer
Apoptotic keratinocytes
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51. 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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52. LICHEN PLANUS

53. 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)

54. Herpes viral infection
Bulla with multinucleate epidermal cells showing herpetic nuclear inclusions
(herpes simplex, varicella zoster)
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55. Molluscum contagiosum (Pox virus)
Viral inclusions
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56. Verruca vulgaris (wart) HPV viral infection
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57. 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)