Copyright M. McMenamin

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 Copyright M. McMenamin

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

ECS Copyright M. McMenamin

Glomus body: modified perivascular smooth muscle cells, involved in temperature regulation

Regional variability in skin Skin of nose – numerous sebaceous glands Skin of forearm Fig. 1.1 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.

ECS Copyright M. McMenamin

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) Copyright M. McMenamin

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

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 Copyright M. McMenamin

Accumulation of mast cells in the dermis Urticaria pigmentosa Accumulation of mast cells in the dermis Copyright M. McMenamin

Dermatographism: urtication (wheals) Positive Darier sign (urtication (wheal) when skin is rubbed Copyright M. McMenamin

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

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 Copyright M. McMenamin

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) Copyright M. McMenamin

Acute dermatitis Spongiosis with epidermal vesicles Copyright M. McMenamin

With continuation of the dermatitis the skin shows features of subacute spongiotic dermatitis with elongated rete ridges and surface scale crust Copyright M. McMenamin

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 Copyright M. McMenamin

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 Copyright M. McMenamin

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. 1.21 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.)

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 Copyright M. McMenamin

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 Copyright M. McMenamin

Pemphigus vulgaris: flaccid blisters and erosions Copyright M. McMenamin

Direct immunofluorescence: Intercellular deposition of IgG and C3 Pemphigus vulgaris Direct immunofluorescence: Intercellular deposition of IgG and C3 Copyright M. McMenamin

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) Copyright M. McMenamin

Bullous pemphigoid: tense blisters on extremities Copyright M. McMenamin

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. 1.21 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

Bullous pemophigoid Linear deposition of IgG and C3 along dermo-epidermal junction Copyright M. McMenamin

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) Copyright M. McMenamin

Dermatitis herpetiformis Granular deposition of IgA along dermo-epidermal junction Copyright M. McMenamin

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 Copyright M. McMenamin

Erythema multiforme: targetoid lesions on hands Copyright M. McMenamin

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) Copyright M. McMenamin

Chronic plaque psoriasis affecting arm and trunk Pustular psoriasis: sterile pustules on an erythematous base Copyright M. McMenamin

Psoriasis showing elongated rete ridges Neutrophils in epidermis (spongiform pustule) Copyright M. McMenamin

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 Copyright M. McMenamin

Nail pitting in psoriasis Copyright M. McMenamin

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 Copyright M. McMenamin

Discoid lupus erythematosus vacuolar interface damage to basal cell layer Apoptotic keratinocytes Copyright M. McMenamin

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 Copyright M. McMenamin

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) Copyright M. McMenamin

Molluscum contagiosum (Pox virus) Viral inclusions Copyright M. McMenamin

Verruca vulgaris (wart) HPV viral infection Copyright M. McMenamin

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)