1. Dermatopathology
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. Hypergranulosis

4. Hyperkeratosis

5. Parakeratosis

6. Papillomatosis

7. Acanthosis

8. Acantholysis

9. Spongiosis

10. Subcorneal cleft

11. Suprabasal cleft

12. Subepidermal cleft

13. Lichenoid interface reaction

14. Perivascular dermatitis

15. Septal panniculitis

16. Lobular panniculitis

17. Sarcoid granuloma

18. Tuberculoid granuloma

19. Foreign body granuloma

20. Necrobiotic granuloma

21. Suppurative granuloma

22. 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

23. Psoriasiform reaction pattern
Psoriasis
Reiter’s syndrome

24. 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

25. 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)

26. 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

27. 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

28. 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

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

30. 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

31. 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

32. 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)

33. 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

34. 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)

35. 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

36. 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%

37. 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

38. 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

39. Lichenoid interface reaction pattern
Lichen planus

40. 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

41. 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

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

45. 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

46. 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

47. 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

48. DIF: intercellular IgG and C3

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

50. 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

51. 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

52. 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)

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

54. 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

55. Subepidermal clefting
Bullous pemphigoid
Dermatitis herpetiformis
Epidermolysis bullosa

56. 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

57. 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

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

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

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

62. 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

63. 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

64. Epidermis
DIF: BMZ granular IgA
Dermis

65. EPIDERMOLYSIS BULLOSA (EB)
Epidermolysis bullosa congenita
Epidermolysis bullosa aquisita

66. 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

67. 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

68. 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

69. 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

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

71. Spongiotic reaction pattern
Allergic contact dermatitis
Seborrheic dermatitis
Atopic dermatitis

72. 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

73. 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

74. 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

75. 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