1. Dermatopathology Inflammatory diseases
Csaba Gyömörei

2. 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

3. 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

4. Psoriasiform reaction pattern
Psoriasis vulgaris
Reiter’s syndrome

5. 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

6. 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)

7. 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

8. Psoriasis Regular epidermal hyperplasia Thinned suprapapillary plates
Parakeratosis
Hypogranulosis/diminished granular layer
Tortuous dilated capillaries
Munro’s abscess
Kogoj’s spongiform pustule
Perivascular lymphocytic infiltrate

9. 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

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

11. 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

12. Erythema multiforme Orthokeratotic stratum corneum Spongiosis
Exocytosis (lymphocytes in epidermis)
Basal vacuolar degeneration
Apoptotic cells
Superficial perivascular lymphocytic infiltrate, sometimes with eosinophiles
Subepidermal cleft in bullous lesion

13. 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)

14. 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

15. 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)

16. 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

17. 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%

18. 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

19. 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

20. Lichenoid interface reaction pattern
Lichen planus

21. 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

22. 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

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

24. 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

25. 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

26. 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

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

28. Subepidermal clefting
Bullous pemphigoid
Epidermolysis bullosa

29. 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

30. 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

31. Bullous pemphigoid subepidermal vesicula/bulla with eosinophils
eosinophilic spongiosis
DIF: BMZ linear C3 (100%) and IgG (65–95%)

32. BULLOUS PEMPHIGOID Immunopathology
Linear C3 and IgG along the dermal–epidermal junction
Circulating antibasement membrane antibodies (75%-90%)
Detection of BPag1 (230 kD) and BPag2 (180 kD) antigens

33. References
Ackerman: Histologic Diagnosis Of Inflammatory Skin Diseases: An Algorithmic Method Based On Pattern Analysis 3rd Edition, 2005
High Yield Pathology: Dermatopathology, Saunders 2011
Inflammatory skin disorders, Demos surgical pathology guides, 2012
Rubin’s pathology : clinicopathologic foundations of medicine, 7th ed. Wolters Kluwer, 2015