Dermatopathology Csaba Gyömörei

Basic patterns of inflammatory skin diseases Perivascular dermatitis Nodular and diffuse dermatitis Vasculitis Vesicular dermatitis Pustular dermatitis Peri-infundibulitis and perifolliculitis Fibrosing dermatitis Subcutan fat: panniculitis

Hypergranulosis

Hyperkeratosis

Parakeratosis

Papillomatosis

Acanthosis

Acantholysis

Spongiosis

Subcorneal cleft

Suprabasal cleft

Subepidermal cleft

Lichenoid interface reaction

Perivascular dermatitis

Septal panniculitis

Lobular panniculitis

Sarcoid granuloma

Tuberculoid granuloma

Foreign body granuloma

Necrobiotic granuloma

Suppurative granuloma

Perivascular dermatitis Perivascular dermatitis is the most common pattern With or without epidermal or, dermoepidermal interface alterations Epidermal changes: psoriasiform acanthosis-psoriasiform dermatitis spongiosis-spongiotic dermatitis Dermoepidermal interface is affected-interface dermatitis vacuolar interface dermatitis lichenoid interface dermatitis

Psoriasiform reaction pattern Psoriasis Reiter’s syndrome

Psoriasis vulgaris Definition: chronic and relapsing disease characterized by erythematous skin lesions covered with silvery white scales Psoriasis affects 1%–2% of the population Localisation: elbow, knees, scalp, gluteal cleft, and lumbosacral area “Auspitz” sign can be seen

Pathogenesis Multifactorial: genetic, immunologic and environmental factors Genetic factors: increased incidence among relatives and offspring of patients with psoriasis 65% concordance for psoriasis in monozygotic twins increased prevalence with certain HLA haplotypes (HLA-B13, HLA-B17, HLA-Bw57 and HLA-Cw6)

Pathogenesis Immunologic factors: T lymphocytes are crucial to the pathogenesis TH1 and TH17 cells in addition to effector CD8+ T cells and antigen-presenting dendritic cells, secrete proinflammatory cytokines (IL-17, IL-23), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), as well as keratinocyte growth factors Environmental factors: physical injury (“Köbner phenomenon”), infection, certain drugs

Histology of psoriasis vulgaris Parakeratosis Hypogranulosis/diminished granular layer Regular epidermal hyperplasia Thinned suprapapillary plates Tortuous dilated capillaries Munro’s abscess Kogoj’s spongiform pustule Perivascular lymphocytic infiltrate

REITER’S SYNDROME Definition Multiorgan autoimmune syndrome characterized by orogenital ulcers, arthritis, conjunctivitis, and psoriasiform skin lesions Clinical features Classic triad of arthritis, nongonococcal urethritis, and conjunctivitis The disease affects young adults Infection typically of the gastrointestinal (e.g., Shigella; also Salmonella, Yersinia) or genitourinary (e.g., Chlamydia) systems precipitates syndrome several days to few weeks later HLA-B27 is a risk factor Associated with HIV disease

Vacuolar interface reaction pattern Erythema multiforme TEN/Stevens Johnson syndrome Lupus erythematosus

ERYTHEMA MULTIFORME (EM) Definition: EM is an acute self limited hypersensitivity reaction to a drug or an infectious agent with characteristic targetoid skin lesions and mucosal involvement Etiologic factors: viral infections (herpes simplex viruses, Mycoplasma) drugs (antibiotics /penicillin, sulfonamides/, anticonvulsants, aspirin, NSAID, antituberculous medications) Clinical features: Occasional prodrome with fever, malaise, nausea Oral involvement characterized by often painful plaques, erosions, and ulcerations over lips, gums, and palate Ocular and genital lesions also seen

Histology of erythema multiforme Orthokeratotic stratum corneum Spongiosis (edema of epidermis) Exocytosis (lymphocytes in epidermis) Apoptotic keratinocytes Basal vacuolar degeneration Superficial perivascular lymphocytic infiltrate, sometimes with eosinophiles Subepidermal cleft in bullous lesion

TOXIC EPIDERMAL NECROLYSIS (TEN)/STEVENS-JOHNSON SYNDROME Definition Severe hypersensitivity reaction demonstrating prominent mucocutaneous necrosis The term Stevens-Johnson syndrome is used when less than 30% of the skin is affected, in TEN 30% or more of skin is involved Causative agents: Predominantly drug-induced (antibiotics /e.g., sulfa-based drugs, penicillin/; anticonvulsants /e.g., carbamazepine, phenytoin, lamotrigine/; NSAIDs) Occasionally infections (Mycoplasma pneumonia)

TOXIC EPIDERMAL NECROLYSIS (TEN)/STEVENS-JOHNSON SYNDROME Clinical features: Prominent involvement of mucosal surfaces (e.g., conjunctiva, oral mucosa, genital mucosa) with blister formation, and eroded blister remnants Typically preceded by prodrome of skin tenderness Potentially life-threatening condition, with mortality in greater than one third of patients Sepsis

LUPUS ERYTHEMATOSUS Definiton: Lupus erythematosus (LE) is an autoimmune disorder which is characterized by autoantibodies and immune complexes It affects multiple organ systems, and classically features mucocutaneous manifestations Three classic forms: chronic cutaneous (discoid) lupus erythematosus (DLE); subacute cutaneous lupus erythematosus (SCLE); systemic lupus erythematosus (SLE)

CHRONIC CUTANEOUS (DISCOID) LUPUS ERYTHEMATOSUS This is the most common subtype DLE is usually limited to the skin Affected areas are above the neck, on the face (especially the malar area), scalp and ears Lesions begin as slightly elevated violaceous papules with a rough scale of keratin They enlarge to assume a disc shape, with a hyperkeratotic margin and a depigmented center The cutaneous lesions may culminate in disfiguring scars Elevated circulating antinuclear antibody (ANA) levels are seen in under 10% of patients

SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS SCLE represents approximately 10% of all cases of LE, and is characterized by widespread nonscarring annular or psoriasiform erythematous scaly lesions occur in the upper chest, upper back and extensor surfaces of the arms Young and middle-aged white women are primerly affected Approximately 50% of patients with SCLE have manifestations of systemic disease, musculoskeletal and renal involvement can occur SCLE can also be associated with Sjögren syndrome, rheumatoid arthritis, medications (drug- induced SCLE) About 70% of patients have circulating anti-Ro (SS-A) antibodies, ANA levels are elevated in 70%

ACUTE SYSTEMIC LUPUS ERYTHEMATOSUS Patients frequently manifest immunologic, hematologic, neurologic, renal disorders as well as serositis, arthritis, and oral ulcers Cutaneous manifestations occur in 75%–88% of patients The typical “butterfly” rash of the malar area of the face is often the first manifestation and may precede the onset of systemic symptoms by a few months Many patients have a maculopapular eruption of the chest and extremities, often following sun exposure Rashes heal without scarring Lesions indistinguishable from discoid lupus may occur ANA levels are elevated in more than 90% of patients

DIRECT IMMUNOFLUORESCENCE (DIF) IN LE (LUPUS BAND TEST) Lesional skin in patients with LE usually demonstrates a combination of immunoglobulins (IgG, IgA, and IgM) and complement (C3) at the basement membrane in a granular pattern along the DEJ IgM is most commonly identified and IgG appears to be the most specific for LE The lupus band test is seen in 60% of patients with SCLE, 50%–94% of patients with SLE and 60%–80% of patients with DLE When the lupus band test is performed on non-lesional skin, a positive result indicates SLE

Lichenoid interface reaction pattern Lichen planus

LICHEN PLANUS Definition: Mucocutaneous condition characterized by pruritic purple, flat-topped papules and plaques clinically and histologically by lichenoid (band-like) chronic inflammation The papules may reveal a delicate white netlike pattern, referred to as Wickham striae The lesions are most commonly seen on the flexor surfaces of the extremities, lumbar area, glans penis, oral mucosa, nail involvement Lichen planus has been associated with viral infections including cases of hepatitis B and C, and HIV LP is occasionally familial and may also accompany autoimmune disorders, such as SLE Lichenoid drug eruption similar, but generally may be photodistributed, lacks both nail involvement, and Wickham’s striae

Histology of lichen ruber planus Ortho-hyperkeratosis Irregular sawtooth acanthosis Hypergranulosis (wedge shaped) Apoptotic keratinocytes ‘‘Civatte- bodies” Band-like lympho-histiocyter infiltrate obscures the DEJ Pigment incontinence Eosinophils in drug induced lichenoid reactions

Intraepidermal clefting Pemphigus vulgaris Paraneoplastic pemphigus Hailey–Hailey disease Darier disease Grover disease

PEMPHIGUS VULGARIS Definition Autoimmune intraepidermal blistering condition affecting the skin and mucous membranes that is mediated by circulating autoantibodies directed against keratinocyte cell surfaces PV antibodies react with desmosomal proteins desmoglein 3 (exclusively in oral disease) and desmoglein 1 (combined with desmoglein 3 in cutaneous disease) triggering a cellular process that results in acantholysis Clinical features PV is most common in people 40–60 years old, although children and elderly also can be affected Drug-induced cases often triggered by captopril, penicillamine

PEMPHIGUS VULGARIS Flaccid vesicles, bullae, and erosions on noninflamed skin May be painful, occasionally pruritic Positive Nikolsky sign (lateral pressure induces epidermal separation) Often symmetrically distributed Mucosal erosions in nearly all patients, oral involvement often the presenting feature May affect conjunctiva and internal mucosae, esophagus, or vagina

Histology of Pemphigus vulgaris Suprabasal cleft due to acantholysis Spongiosis in early lesion, eosinophil spongiosis (eosinophils in spongiotic epidermis) Follicular involvement Superficial perivascular mononuclear infiltrate DIF: intraepidermal intercellular IgG and C3

DIF: intercellular IgG and C3

PEMPHIGUS VULGARIS Immunpathology Direct immunofluorescence: IgG, C3 in an intercellular pattern around keratinocytes of the epidermis-“chicken wire” pattern appearance

HAILEY-HAILEY DISEASE (FAMILIAR BENIGN PEMPHIGUS) Autosomal dominantly inherited skin disease (genodermatosis) Caused by calcium channel pump mutation (ATP2C1) It is characterized by symmetrically distributed, pruritic moist intertriginous plaques in the axillary, groin, genital, perianal, chest, and neck regions Bacterial and fungal superinfection leads to malodor • Lesions usually appeare during adolescence, but may asymptomatic until 4-5 decades of life

Histology of Hailey-Hailey disease • full-thickness acantholysis of an acanthotic epidermis-dilapidated brick wall appearance • Usual absence of adnexal involvement (compare with pemphigus vulgaris) • Associated variable patchy acute or chronic inflammatory cell infiltrate • Direct immunofluorescence test negative

DARIER’S DISEASE (KERATOSIS FOLLICULARIS) Autosomal dominantly inherited genodermatosis Caused by mutation (ATP2A2) in calcium channel pump of sarcoplasmic reticulum (SERCA2 protein) Coalescent brownish, erythematous keratotic papules in seborrheic areas (central chest, scalp, central face, intertriginous regions)

Histology of Darier’s disease • Suprabasilar acantholysis • Dyskeratotic cells: corps ronds and corps grains • Direct immunofluorescence test negative

GROVER’S DISEASE (TRANSIENT ACANTHOLYTIC DERMATOSIS) Idiopathic pruritic disease characterized by pruritic discrete papulovesicles on the chest, back, and thighs usually in middle-aged or elderly males may be chronic and recurrent

Subepidermal clefting Bullous pemphigoid Dermatitis herpetiformis Epidermolysis bullosa

BULLOUS PEMPHIGOID Definition Immunobullous subepidermal blistering condition Clinical features Pruritic tense bullae without classic Nikolsky sign Distributed over abdomen, inner thighs, and flexural aspects of the limbs Occasionally drug-related

BULLOUS PEMPHIGOID Complementfixing IgG antibodies are against BPAG1 and BPAG2 BPAG1 is a 230-kd protein in the intracellular portion of the basal cell hemidesmosome BPAG2 is a 180-kd protein that traverses the plasma membrane and extends into the upper lamina lucida of basal membran

Histology of bullous pemphigoid subepidermal vesicula/bulla with eosinophils eosinophilic spongiosis DIF: BMZ linear C3 (100%) and IgG (65–95%)

DIF: BMZ linear C3 and IgG Epidermis Dermis DIF: BMZ linear C3 and IgG

BULLOUS PEMPHIGOID Immunopathology Linear C3 and IgG along the dermal–epidermal junction Circulating antibasement membrane antibodies (75%-90%)

DERMATITIS HERPETIFORMIS DUHRING (DHD) It is a rare, chronic subepidermal blistering disorder affects young adults gluten-sensitive enteropathy detected histologically in vast majority of patients   DHD is characterized by pruritic, grouped urticarial plaques, papules and vesicles distributed symmetrically over extensor surfaces of elbows, knees, buttocks, back

Histology of DHD • Subepidermal blister • Neutrophil-rich infiltrate in blister cavity and dermis • Eosinophils sometimes evident in older lesions • Neutrophil microabscesses within edematous dermal papillae in the adjacent skin or featured in very early lesions • Direct immunofluorescence (perilesional skin): granular IgA deposition within dermal papillae, C3 also present • Target antigen currently suspected to be epidermal transglutaminase 3 • IgA endomysial antibodies positive in majority of cases

Epidermis DIF: BMZ granular IgA Dermis

EPIDERMOLYSIS BULLOSA (EB) Epidermolysis bullosa congenita Epidermolysis bullosa aquisita

Epidermolysis bullosa congenita Heterogeneous group of inherited congenital blistering conditions Epidermolysis bullosa simplex (EBS): mutation in keratins 5 and 14; autosomal dominant inheritance Hemidesmosomal epidermolysis bullosa (HEB): mutations in BP180, plectin, α6β4 integrin; autosomal recessive inheritance Junctional epidermolysis bullosa (JEB): mutation in laminin 5; autosomal recessive inheritance Dystrophic epidermolysis bullosa (DEB): mutation in collagen VII; autosomal dominant or autosomal recessive inheritance

Epidermolysis bullosa congenita EBS: defect in the basal layer of the epidermis causes peeling skin noted usually at birth, induced by trauma; palms and soles usually affected HEB: includes cases associated with pyloric atresia and late-onset muscular dystrophy DEB: may be severe, with scarring and increased risk of squamous cell carcinoma

Epidermolysis bullosa congenita Complications: contractures, scarring, infection sepsis important cause of death in infancy high risk of squamous cell carcinoma in recessive dystrophic variant Histology Generally noninflammatory blisters, cannot distinguish subtypes on the basis of simple histology Dermis with minimal or no inflammation Precise diagnosis with electron microscopy HEB: split within hemidesmosome JEB: split within the lamina lucida

Epidermolysis bullosa aquisita Rare autoimmune blistering disease caused by antibodies to collagen VII Arises in adulthood and the elderly localized noninflammatory (classic) variant, generalized inflammatory variant, and mucosal variant Affected areas: hands, elbows, knees, buttocks Histology: subepidermal blister Cell free and inflammatory variant DIF: C3 and IgG along dermal–epidermal junction in a linear pattern

Type IV collagen Bullous pemphigoid Epidermolysis bullosa aquisita McKee's Pathology of the Skin. – 4th ed.

Spongiotic reaction pattern Allergic contact dermatitis Seborrheic dermatitis Atopic dermatitis

ALLERGIC CONTACT DERMATITIS Cutaneous delayed hypersensitivity reaction to exogenous antigen Common contactants include nickel, plants (Rhus), fragrance, formaldehyde Eczematous reaction pattern at areas in contact with the offending antigen Acutely, exposed areas may be blistering, brightly erythematous edematous papules and plaques, often with excoriation, sometimes with crusting With time, areas become xerotic, develop more prominent scale, and may leave postinflammatory hyper/hypopigmentation

ALLERGIC CONTACT DERMATITIS Histology: •Acute: prominent epidermal spongiosis often with vesiculation, lymphocytic exocytosis, conspicuous epidermal Langerhans cells, may form microabscesses, superficial dermal perivascular lymphohistiocytic infiltrate with eosinophils, papillary dermal edema • Subacute: focal parakeratosis, epidermal spongiosis less conspicuous, mild epidermal hyperplasia, superficial dermal chronic inflammation • Chronic: focal parakeratosis, psoriasiform epidermal hyperplasia, spongiosis much less prominent or absent, papillary dermal fibrosis

ERYTHEMA NODOSUM (EN) EN is the most common type of panniculitis It has a peak incidence in the 2–3 decades of life Women are more common affected than men Tender, erythematous nodules or plaques develop, most commonly involve the shins Fever, arthralgias and fatigue may also occur It is probably a hypersensitivity response to underlying antigens it is associated with infections, drugs, malignancies and inflammatory disorders (inflammatory bowel disease, sarcoidosis) In children, it is most often associated with streptococcal infections

Histology of EN Early lesions have more inflammation (neutrophils) and less fibrosis Later lesions demonstrate septal thickening, lymphocytes, histiocytes, eosinophils, and multinucleated giant cells Miescher’s radial granulomas: aggregates of small histiocytes around central cleft No vasculitis