Inflammatory Dermatopathology: A Survival Kit for Surgical Pathologists

Steven D. Billings, MD Cleveland Clinic, Cleveland, OH [email protected]

Inflammatory Dermatopathology

• Difficult • Overlapping histologic features • Impenetrable terminology • Specific diagnosis often elusive

Inflammatory Dermatopathology How to produce good reports • Diagnostic category • Tumor vs. rash? • Which inflammatory pattern? • Clinical presentation • Information regarding clinical features can influence histologic interpretation • Communication with clinicians crucial • Telephone 2nd most important tool

1 Ideal Dermatopathology Report

• Microscopic description • Diagnosis • Specific diagnosis often not possible • Often ―descriptive‖ diagnosis • Example: ―Spongiotic ‖ • Note • Explain differential diagnosis • What diagnosis is favored • Additional comments as needed

Pattern Recognition

• Skin has limited ways to react • Predominant pattern of inflammatory infiltrate helps define diagnostic categories • Patterns can overlap • Some entities can have a variety of patterns

General Concepts

• Pattern recognition • Epidermal predominant vs. dermal predominant • Epidermal changes trump dermal changes • Distribution of the inflammatory infiltrate • Superficial vs. superficial and deep • Location: perivascular, interstitial, nodular • Nature of inflammatory infiltrate • Mononuclear (lymphocytes and histiocytes) • Mixed (mononuclear and granulocytes) • Granulocytic • Correlation with clinical presentation

2 Principle Patterns: Epidermal Changes Predominant • Spongiotic pattern • Psoriasiform pattern • Spongiotic and psoriasiform often co-exist • Interface pattern • Basal vacuolization • Perivascular infiltrate or • Lichenoid infiltrate

Principle Patterns: Dermal Changes Predominant • Superficial perivascular • Superficial and deep perivascular • Interstitial pattern • Palisading granulomatous • Nodular and diffuse • Sclerosing pattern

• Panniculitis • Bullous disease • Miscellaneous

Spongiotic Dermatitis

3 Case

A 40-year-old woman presented with linear blisters on both forearms.

4 Diagnosis: Spongiotic Dermatitis

5 Spongiotic Dermatitis

• Three phases • Acute • Subacute • Chronic • Different but overlapping histologic features

Spongiotic Dermatitis

• Acute spongiotic dermatitis • Normal ―basket-weave‖ stratum corneum • Pale keratinocytes • • Spongiotic vesicles (variable) • Papillary dermal edema • Variable superficial perivascular infiltrate of lymphocytes often with some eosinophils

6 Spongiotic Dermatitis

• Subacute spongiotic dermatitis • • Diminished granular layer • Spongiosis • Acanthosis (overlap with psoriasiform pattern) • Variable superficial perivascular infiltrate of lymphocytes often with some eosinophils • Less edema

7 Spongiotic Dermatitis

• Chronic spongiotic dermatitis • • Parakeratosis • Irregular granular layer • Acanthosis (overlap with psoriasiform) • Minimal to mild spongiosis • Variable perivascular infiltrate • Dermis may be fibrotic

8 Common Clinical Types of Spongiotic Dermatitis • Eczema Dermatitis Family • • • • Dyshidrotic dermatitis (hand/foot dermatitis) • () • Eczematous

Eczema

• Clinical term • Histologically spongiotic dermatitis • Specific diagnosis dependent on correlation with clinical presentation

• CLINICAL SUBTYPES ARE HISTOLOGICALLY INDISTINGUISHABLE

Atopic Dermatitis

• Chronic pruritic, relapsing papular dermatitis • Associated with history of asthma, allergic rhinitis (atopy) • Predilection for flexural areas, especially in children

9 Allergic Contact Dermatitis

• Clinical • Erythematous , plaques and sometimes vesicles • May have linear pattern • Secondary to type IV delayed hypersensitivity reaction • Examples: nickel allergy, poison ivy • Microscopic • Typical spongiotic dermatitis • May have Langerhans cell microabscesses

10 11 Irritant Contact Dermatitis

• Clinical • Erythematous papules and vesicles • Secondary to direct irritant effect • Example: diaper rash • Microscopic • Typical spongiotic dermatitis • Ballooning degeneration of keratinocytes

Nummular Dermatitis

• Common form of eczema that is biopsied • Clinical • Pruritic round to oval patches and plaques • Often on extremities • Microscopic • Psoriasiform and spongiotic • Can be classified as psoriasiform dermatitis • Differential diagnosis •

12 Dyshidrotic Eczema (Pomphylox)

 Symmetric involvement of hands and/or feet  Often vesicular  Clinical and histologic differential diagnosis: vesicular infection

13 Id Reaction (Autoeczematization) • Widespread dissemination of previously localized ―eczematous‖ process • Triggers • Dermatophyte infection • Stasis dermatitis • Discontinuation of systemic steroids • Others • Abnormal immune response to skin antigens

14 Eczematous Drug Reaction

 Clinical • 5-10% of drug reactions may be eczematous in nature • Widespread eruption • Microscopic • Typical spongiotic dermatitis

Practical Tips for Eczematous Dermatitis

• Dx: ―spongiotic dermatitis, see note‖ • Dx in cases with acanthosis: ―spongiotic psoriasiform dermatitis, see note‖ • Note: ―The histologic features are compatible with an eczematous dermatitis. The DDx could include….. Clinicopathologic correlation is recommended.‖ • Tips • Eliminate where possible more specific entities • Neutrophils in stratum corneum or : exclude dermatophytosis or psoriasis • Clinical history can be helpful • Langerhans cell microabscess: suggest contact dermatitis

Other Forms of Spongiotic Dermatitis • Vesicular dermatophytosis • Stasis dermatitis •

15 Case

68 year-old woman with crusted, red scaly plaques on lower legs

16 Stasis Dermatitis

• Clinical • Lower extremities associated with venous insufficiency • May develop ulcers • May clinically mimic a neoplasm (e.g. SCC) • Microscopic • Subacute to chronic spongiotic dermatitis • Significant acanthosis • Lobular proliferation of thick-walled dermal vessels • Extravasated erythrocytes, siderophages, perivascular lymphocytes • Variable dermal fibrosis

17 Stasis Dermatitis

• Differential diagnosis • Eczematous dermatitis • Kaposi sarcoma • Tips • High index of suspicion • Vascular changes key feature

18 Case

29 year-old medical student with red scaly plaques on trunk

19 Pityriasis Rosea

• Clinical • Affects young adults • Round to oval salmon-colored herald patch • Widespread, symmetric eruption on trunk . Microscopic • Subacute spongiotic dermatitis • Mounds of parakeratosis • Superficial perivascular mononuclear cell infiltrate • Extravasation of erythrocytes in papillary dermis

20 Pityriasis Rosea

• Differential diagnosis • Eczematous dermatitis, guttate psoriasis • Tips: • Parakeratotic mounds key feature • Sign out descriptively in absence of good history • Dx: Spongiotic dermatitis • Note: Given the discrete mounds of parakeratosis, the histologic differential diagnosis would include pityriasis rosea. CPC recommended.

Psoriasiform Dermatitis

• Pattern often co-exists with spongiosis • Entities in psoriasiform dermatitis ddx • Psoriasis • Subacute to chronic spongiotic dermatitis • Stasis dermatitis • / nodularis • Dermatophytosis •

Psoriasiform Dermatitis

21 Case

A 35-year-old man presented with large plaques on his elbows and trunk.

22 23 Psoriasis

Psoriasis vulgaris • Clinical • Usually presents in 2nd-3rd decades • Erythematous plaques with silvery scale • Extensor surfaces, scalp, gluteal cleft, glans penis • Nail pitting and yellow discoloration • Arthritis 1-5%

Psoriasis Vulgaris

• Microscopic • Uniform acanthosis with elongated rete ridges • Absent (diminished) granular layer • Prominent parakeratosis • Neutrophils in stratum corneum (Munro‘s microabscess) and/or epidermis (pustules of Kogoj) • Suprapapillary plate thinning • Dilated, tortuous papillary dermal vessels

24 Psoriasis Vulgaris

• Differential Diagnosis • Nummular dermatitis • Contact dermatitis • Seborrheic dermatitis • Pityriasis rubra pilaris • Dermatophytosis

Psoriasis Vulgaris

• Practical tips • Eosinophils absent in psoriasis (intravascular eosinophils don‘t count) with one exception • Epidermal hyperplasia not always uniform • Impetiginization not seen • May see some granular layer in rubbed psoriasis • Some features may be absent in partially treated psoriasis • Descriptive dx: psoriasiform dermatitis

25 Psoriasis Variants

Pustular psoriasis • Clinical • Associated with pregnancy and discontinuation of systemic steroids • Rapid onset • Microscopic • Epidermal hyperplasia rare • Granular layer diminished but not absent • Large neutrophilic in epidermis and stratum corneum • Little spongiosis • Differential Diagnosis • , eczematous dermatitis with secondary impetiginization, acute generalized exanthematous pustulosis (AGEP), IgA

http://www.internationaleczema-psoriasisfoundation.org

26 Psoriasis Variants

Guttate psoriasis • Clinical • Rapid onset • Widespread disease • Small scaly plaques • Antecedent streptococcal infection

27 Psoriasis

Guttate psoriasis • Microscopic • Minimal acanthosis • Diminished granular layer (variable) • Focal mounds of parakeratosis with neutrophils • Differential Diagnosis • Pityriasis rosea

TNF-α Inhibitor-induced psoriasis

• TNF-α inhibitors • Examples: infliximab, adalimumab, certolizumab • Used to treat inflammatory bowel disease, rheumatoid arthritis, psoriasis • Can induce psoriasis • Histologically resembles psoriasis vulgaris, but has eosinophils

28 29 TNF-α Inhibitor-induced psoriasis

• Differential diagnosis: spongiotic dermatitis (especially nummular dermatitis), dermatophyte infection • Practical tips • Exclude fungal infection with PAS or GMS stain • If the biopsy looks like psoriasis but there are eosinophils, contact clinician to get medication history

Dermatophytosis

• Clinical • Annular scaly plaques with central clearing • Usually on trunk • Microscopic • Neutrophils in stratum corneum • Parakeratosis • Hyphae in stratum corneum (usually seen with PAS or GMS stain) • Acanthosis

Dermatophytosis

• Microscopic • Variable spongiosis • Superficial perivascular infiltrate with some eosinophils • Differential Diagnosis • Psoriasis, spongiotic dermatitis

30 31 Practical Tips

• PAS/GMS stains are cheap • Always consider dermatophytosis when neutrophils are in stratum corneum • Eosinophils usually conspicuous in dermis • Consider dermatophyte infection with a clinical history of poor response to topical steroids

Pityriasis Rubra Pilaris

• Clinical • Hyperkeratotic perifollicular papules with surrounding yellow-orange erythema • Islands of spared uninvolved skin • Palmar and or plantar keratoderma

32 Pityriasis Rubra Pilaris

• Microscopic • Hyperkeratosis alternating with parakeratosis vertically and horizontally (―checkerboard pattern‖) • Diffuse acanthosis very similar to psoriasis vulgaris • Absence of neutrophils • Intact granular layer • No suprapapillary thinning • Follicular plugging • Mild lymphohistiocytic, superficial perivascular infiltrate • Differential Diagnosis • Psoriasis vulgaris

33 Practical Tips

• Absence of neutrophils • Granular layer intact • Lack of supra-papillary plate thinning

Case

A patient with chronic renal failure presented with numerous pruritic nodules.

34 35 Diagnosis:

Lichen Simplex Chronicus and Prurigo Nodularis • Clinical • Spectrum of same dermatologic disease • Secondary to persistent rubbing/scratching • Lichen simplex chronicus presents as pruritic indurated plaques • Prurigo nodularis presents as pruritic nodules • Lesions occur only where the skin can be reached: posterior scalp, ankle, shin, forearm, anterior thigh, genitalia • Can develop as a secondary change in underlying dermatitis

36 Lichen Simplex Chronicus and Prurigo Nodularis • Microscopic: • Prominent compact hyperkeratosis • Variable parakeratosis • Thickened granular layer • Acanthosis, sometimes with pseudoepitheliomatous pattern • Vertical fibrosis of papillary dermis • Mild perivascular lymphocytic infiltrate • Looks like acral skin (hairy palm sign)

37 38 Lichen Simplex Chronicus and Prurigo Nodularis • Differential Diagnosis • Psoriasis • • Verruca vulgaris • Chronic spongiotic dermatitis • Sometimes squamous cell carcinoma

Practical Tips

• Acral skin in non-acral location • ―Hairy palm‖ sign • Clinical history: is it itchy? • Descriptive diagnosis • Psoriasiform dermatitis with f/o LSC/PN • May be superimposed on spongiotic dermatitis

Psoriasiform Dermatitis: Practical Tips • When histologic features and clinical history solid • Diagnosis: specific diagnosis • Histologic features or history less clear-cut • Diagnosis: psoriasiform dermatitis • Note: • Provide differential diagnosis • What do you favor? (e.g. psoriasis vs. nummular dermatitis) • Eliminate fungal infection (PAS)

39 Interface Pattern

Characteristic findings • Basal vacuolization at dermal-epidermal junction • Dyskeratotic (necrotic) keratinocytes • Lichenoid or perivascular infiltrate

Interface Dermatitis with lichenoid infiltrate

40 Case

A 25-year-old woman presents with pruritic papules on her wrists.

41 Diagnosis: Lichen Planus

42 Lichen Planus

• Clinical • Pruritic violaceous, polygonal papules • Predilection for flexural surfaces of wrists and ankles • May be widespread • Oral lichen planus reticulated appearance

Lichen Planus

• Microscopic • Hyperkeratosis without parakeratosis • Acanthosis with wedge-shaped • Interface change with dense band-like lymphocytic infiltrate • ―Saw-tooth‖ rete pegs • Scattered dyskeratotic cells

43 Lichen Planus

• Microscopic variants • Atrophic • thinned epidermis • subtle interface change • subtle wedge-shaped hypergranulosis • Hypertrophic • similar to classic lichen planus • more prominent acanthosis

44 Lichen Planus

• Oral lichen planus • Absent or subtle granular layer • Lichenoid infiltrate (sometimes less prominent)

45 Lichen Planus

• Differential Diagnosis • Classic • lichenoid benign keratosis • fixed drug reaction • lichenoid drug eruption • lichenoid graft vs. host disease • lichenoid pigmented purpuric dermatosis

Lichen Planus

• Differential Diagnosis • Atrophic • resolving lichenoid benign keratosis • erythematosus • dermatomyositis • Hypertrophic • lichenoid benign keratosis • squamous cell carcinoma • prurigo nodule

46 Practical Tips

• Parakeratosis absent in lichen planus • Eosinophils may be present but are not numerous • If prominent, consider lichenoid drug reaction • Solitary lesions that look like lichen planus: lichenoid benign keratosis • Oral lichen planus more subtle

Lichenoid Drug Eruption

• Clinical • Widespread violaceous papules • May occur weeks to months after initiation of drug therapy • May progress to exfoliative dermatitis

Lichenoid Drug Eruption

47 Lichenoid Drug Eruption

• Microscopic • Very similar to lichen planus • Lichenoid infiltrate with eosinophils • Often some parakeratosis • Differential Diagnosis • Lichen planus, fixed drug eruption • Practical tips • Look for eosinophils and parakeratosis

48 Fixed Drug Eruption

• Clinical Presentation • History of identical lesions occurring in the identical locations • Sharply demarcated macule develops within hours of ingesting a drug • Lesion evolves from red to violaceous to dark brown; blistering may occur • Barbiturates, phenolphthalein, tetracyclines

Fixed Drug Eruption

• Microscopic • Basket weave stratum corneum or parakeratosis • Lichenoid infiltrate of lymphocytes admixed with some eosinophils • Interface change with dyskeratotic keratinocytes • Melanophages seen in older or recurrent lesions

49 Fixed Drug Eruption

• Differential Diagnosis • • Lupus erythematosus • Lichenoid drug reaction • Tips • Eosinophils • Melanophages • Clinical history: solitary or localized, history of recurrence

50 Case

A 63-year-old man presented with a widespread erythematous papular eruption.

51 Morbilliform drug eruption

• Clinical • Blanchable • Symmetric, widespread macular or papular eruption • Microscopic • Mild vacuolar change (sometimes absent) • Mild (sometimes absent) • Blood vessel ectasia • Superficial perivascular infiltrate of lymphocytes and eosinophils

52 Morbilliform Drug Eruption

• Differential Diagnosis • Graft vs. host disease • Lupus erythematosus • Dermatomyositis • Viral

53 Morbilliform Drug Eruption

• Practical Tips: • Interface change often absent • Eosinophils • Descriptive dx: • Interface dermatitis with superficial perivascular mixed cell infiltrate, see note • Superficial perivascular mixed cell infiltrate, see note • Note: The histologic features are consistent with a dermal hypersensitivity reaction such as a drug eruption. Clinicopathologic correlation is recommended.

Case

A 24-year-old woman presented with a papular eruption on both hands. Some of the papules had central necrosis.

54 Erythema Multiforme

• Clinical • Self-limiting episodic eruptions • Erythematous macules, papules and targetoid lesions • Extensor surfaces, palms, soles, and oral mucosa • Variants • Minor (erythema multiforme) • Major (Stevens-Johnson syndrome) based on extent of mucosal involvement • Associated with HSV, Mycoplasma, and drugs (sulfonamides)

55 Erythema Multiforme

• Microscopic • Normal basket-weave stratum corneum • Spongiosis • Dyskeratotic cells at all levels of epidermis • Basal vacuolization • Mild superficial perivascular lymphohistiocytic infiltrate (sometimes eosinophils) • Exocytosis of lymphocytes • Epidermal necrosis (seen in older lesions)

Erythema Multiforme

• Differential diagnosis • Toxic epidermal necrolysis • Drug eruption • Viral • Dermatomyositis • Lupus erythematosus

56 Toxic Epidermal Necrolysis

• Clinical • Widespread tender macular erythematous eruption with vesicles and bullae • Nikolsky‘s sign (epithelial detachment with mild pressure) • Mortality 25-50% • Microscopic • Similar to erythema multiforme • Detachment of epidermis from dermis • Scant superficial perivascular infiltrate

57 Toxic Epidermal Necrolysis

• Differential Diagnosis • Erythema multiforme • Fixed drug eruption • Staph scalded skin syndrome • Clinically mimics TEN • Can be resolved on frozen section

The late night frozen section : TEN vs. staph scalded skin syndrome

• Staph scalded skin syndrome • Caused by toxin • Toxin causes split in upper epidermis • Not the absence of granular layer and stratum corneum • No interface change

Practical Tips: EM and TEN

• Necrotic keratinocytes, normal stratum corneum • Distinction between EM and TEN requires clinical information • SJS and TEN: medical emergency

58 Case

A 45-year-old woman presented with a plaque on her forehead. A previous biopsy from this area 4 years earlier was diagnosed as squamous cell carcinoma.

59 60 Lupus Erythematosus

• Clinical • Chronic (discoid) • Well-demarcated scaly plaques • Erythematous to hyper or hypopigmented • Usually on head/neck (sun-exposed skin) • Most patients with skin only disease • Subacute • Scaly erythematous, often annular plaques • Upper trunk, extensor surfaces of arms • Positive ANA 75%

Lupus Erythematosus

• Clinical • Acute • Associated with systemic lupus erythematosus • Erythematous lesions • Malar rash • Positive ANA and anti-DNA antibodies

61 62 Lupus Erythematosus

• Microscopic • Histologic overlap between subtypes • Basal vacuolization • Perivascular and periadnexal mononuclear cell infiltrate • Epidermal (often) • Increased dermal mucin • Differential Diagnosis • Erythema multiforme, lichen planus, dermatomyositis

63 Tumid Lupus Erythematosus

• Clinical • Juicy erythematous plaques • Microscopic • Superficial and deep infiltrate • Perivascular and periadnexal • Increased dermal mucin • Little to no interface change

64 Dermatomyositis

• Clinical • Systemic disease with muscle weakness (some patients have only cutaneous disease) • Heliotrope periorbital discoloration • Violaceous rash on face and neck • Periungual erythema • Gottron‘s papules on hands

65 Dermatomyositis

• Microscopic • Basal vacuolization • Superficial perivascular mononuclear cell infiltrate, usually mild • Increased dermal mucin • Differential diagnosis • Lupus erythematosus • Graft vs. host disease

66 Practical Tips LE and DM

• Eosinophils absent • Mucin helpful but non-specific • Tumid LE lacks interface change • LE may have superficial or superficial and deep perivascular patterns • ‗AK‘ clue: reactive atypia in keratinocytes • DM generally does not have deep infiltrate • DM cannot be distinguished from LE • Descriptive Dx: interface dermatitis • Note: The ddx would include connective tissue disease such as lupus erythematosus

Graft vs. Host Disease

• Clinical • Acute GVHD • Usually 2-4 weeks after bone marrow transplant • Rarely solid organ transplants • Macular erythema on trunk, neck, hands, and feet • May form blisters • Systemic symptoms • Chronic GVHD • Months to years after bone marrow transplant • Lichenoid: violaceous papules on extremities, palms, and soles • Sclerodermoid: presents as dermal sclerosis

Graft vs. Host Disease

• Microscopic • Acute GVHD • Grade 0 : normal epidermis • Grade 1: Basal vacuolization, mild superficial perivascular lymphocytic infiltrate • Grade 2: Same as Grade 1 changes with dyskeratotic keratinocytes, satellite cell necrosis • Grade 3: Same as grade 2 but with cleft formation between dermis and epidermis • Grade 4: Same as Grade 3 but with complete separation of epidermis from dermis

67 Graft vs. Host Disease

• Microscopic • Chronic Lichenoid • Resembles lichen planus • Chronic Sclerodermoid • Resembles / • Differential Diagnosis • Acute GVHD: drug eruption, lupus erythematosus, dermatomyositis, viral exanthem • Lichenoid GVHD: lichen planus • Sclerodermoid GVHD: morphea/scleroderma

68 Practical Tips

• Be careful: Grade 1 • Rare to see GVHD earlier than 14 days • May see late onset acute GVHD in some settings • Eosinophils may be seen in GVHD • Multiple levels may be needed

69 Case

A 15-year-old boy presents with numerous crusted papules.

70 71 Pityriasis Lichenoides et Varioliformis Acuta (PLEVA or Mucha-Haberman Disease)

• Clinical • Recurrent crops of flesh colored to erythematous papules • Lesions evolve into vesicles, hemorrhagic lesions and crusted ulcerations • Resolution leaves varioliform scars

PLEVA

• Microscopic • Epidermal changes variable • Typical: Scale , interface change, dyskeratosis, exocytosis of lymphocytes • Early: no epidermal changes • Late: epidermal ulceration • Wedge-shaped dermal infiltrate of small lymphocytes with occasional neutrophils • Some dermal hemorrhage

72 PLEVA

Differential Diagnosis • Pityriasis lichenoides chronica (spectrum of same disease) • Less inflammation • Pityriasis rosea • • Lymphomatoid papulosis

73 Practical Tips

• High index of suspicion • Interface change with hemorrhage usually present • Clinical history

Superficial Perivascular Dermatitis

• Inflammatory infiltrate confined to upper dermis • Little epidermal change • Infiltrate primarily around vessels • Nature of infiltrate • Mononuclear cells • Mixed granulocytic and mononuclear • Predominantly granulocytic

74 Superficial Perivascular Dermatitis

• Morbilliform drug eruption • Postinflammatory pigment alteration • Progressive pigmented purpuric eruption (Schamberg‘s Disease) • Urticaria • Urticaria Pigmentosa (mastocytosis) • Leukocytoclastic

Case

37 year-old woman with hypopigmented macules

75 Postinflammatory Pigment Alteration • Clinical • Hyperpigmented or hypopigmented macules and patches • Result of pre-existing inflammatory disorder that has resolved

Post-Inflammatory Pigment Alteration • Microscopic • Minimal to mild superficial perivascular lymphohistiocytic infiltrate • Scattered melanophages • Little or no epidermal changes typically • Melanocytes still present in epidermis

76 Postinflammatory Pigment Alteration • Differential Diagnosis • • Regressed melanocytic lesions • Pigmented purpuric eruption (Schamberg‘s disease) • Practical tips • Inflammatory infiltrate mild • Consider S100 or Melan A • Dx: ―Mild superficial perivascular mononuclear cell infiltrate with melanophages‖ • Note: c/w post-inflammatory pigment alteration

Case

25 year-old woman with long history of hyperpigmented papules

77 78 Mastocytosis

• Clinical • 4 clinical forms: urticaria pigmentosa, macularis eruptiva perstans (TMEP), mastocytoma, systemic mast cell disease • Urticaria pigmentosa: Erythematous to tan macules and papules • Mastocytoma: solitary lesion • TMEP: pigmented macules with telangiectasia • May present in childhood or adulthood • Lesions urticate when stroked (Darier‘s sign)

Urticaria Pigmentosa (Mastocytosis) • Microscopic • Superficial perivascular infiltrate predominantly composed of mast cells • Mast cell infiltrate can be quite dense with a superficial and deep distribution • Special stains often necessary to demonstrate mast cells • Giemsa, Leder, and immunostains for tryptase and CD117

79 Mastocytosis

• Differential Diagnosis • Superficial perivascular pattern: viral exanthema, non-specific perivascular infiltrate, drug eruption, normal skin • Dense superficial and deep pattern: intradermal , Langerhans cell histiocytosis, lymphoma

Practical Tips

• High index of suspicion • Dx = ―mastocytosis‖ • Special stains • Giemsa or Leder • Tryptase or CD117 (c-kit) • Rule of thumb: >15/HPF • CD25 expression associated with systemic disease • T-cells also CD25+

80 Urticaria

• Clinical • Transient edematous pruritic plaques () • Typically resolve in 24 hours • Microscopic • Normal epidermis • Dermal edema • Superficial perivascular infiltrate of lymphocytes and eosinophils and sometimes a few neutrophils • Sometimes a deeper component present

81 Urticaria

• Differential Diagnosis • Urticarial phase of • Arthropod bite reaction • Drug eruption Tips Remember urticaria is transient • If > 24 hours, think about • urticarial bullous pemphigoid • other dermal hypersensitivity reactions • Infiltrate may have deep component • Clue: neutrophils in vascular lumens

82 Case

40 year-old man with numerous red-brown macules on lower legs

Progressive Pigmented Purpuric Eruption (Schamberg‘s Disease) • Clinical • Red-brown macules • Most commonly on lower legs • Microscopic • Little epidermal change; occasionally may have some spongiosis • Mild superficial lymphocytic infiltrate with extravasated erythrocytes and siderophages • Occasionally may have a lichenoid infiltrate • No fibrinoid necrosis

83 Pigmented Purpuric Dermatosis • Clinical • Red-brown macules • Most commonly on lower legs • Variant • Schamberg‘s (most common) • Lichenoid purpura of Gougerot and Blum • Eczematoid-like purpura of Doucas and Kapetanakis • Purpura annulare telangiectoides of Majocchi • Lichen aureus

84 Lichen Aureus

Progressive Pigmented Purpuric Eruption (Schamberg‘s Disease) • Differential Diagnosis • Stasis dermatitis • Post-inflammatory pigment alteration • Leukocytoclastic vasculitis • • Tips • No fibrin deposition in blood vessels • Siderophages not melanophages • Lichenoid variant

Leukocytoclastic Vasculitis • Clinical Presentation • Palpable purpura • Causes: sepsis, collagen vascular diseases, drugs, lymphoma and myeloma, idiopathic (Henoch-Schönlein purpura)

85 Henoch-Schönlein Purpura

• Primarily affects children • Purpuric skin lesions • Abdominal pain/gastrointestinal bleeding • Renal abnormalities • Associated with IgA immune complexes

Leukocytoclastic Vasculitis

• Microscopic features • Superficial perivascular infiltrate (may have deep component) • Predominantly neutrophils • Leukocytoclasis • Extravasated erythrocytes • Fibrinoid necrosis of blood vessels

86 IgA

Leukocytoclastic Vasculitis

• Differential diagnosis • Sweet‘s syndrome • Secondary vasculitic changes • Erythema elevatum diutinum • Granuloma faciale • Practical tips • May have deep component • May not see all features • IgA immune complexes supportive of HSP • May see secondary vasculitic changes under ulcers

87 Superficial and Deep Perivascular Infiltrate • Little epidermal change • Predominantly perivascular infiltrate • Superficial and deep distribution

Superficial and Deep Perivascular Infiltrate • Lupus erythematosus (Tumid variant) • Pityriasis Lichenoides et Varioliformis Acuta (PLEVA) (early lesions) • Lymphomatoid Papulosis (LYP) • Arthropod Bite Reaction • Dermal hypersensitivity reaction NOS • Sweet‘s Syndrome

88 Case

A 24-year-old woman presented with a recurrent papular eruption

89 CD 30

90 Diagnosis Lymphomatoid Papulosis

Lymphomatoid Papulosis (LYP)

• Clinical • Multiple papules or nodules • Spontaneous regression or waxing-waning of lesions that heal with superficial scars • Lesions do not grow to a diameter larger than 3 cm during 3 months of observation without treatment • Absence of lymphadenopathy • Approx. 10% of patients may develop lymphoma (MF, HD, CD30+ALCL)

91 Lymphomatoid Papulosis • Microscopic: 3 histologic types • Type A • Wedged shape, superficial and deep • Scattered atypical CD30+ cells • Mixed inflammatory background (eosinophils, neutrophils, lymphocytes) • Type B (MF-like) (very rare) • Band-like distribution • Atypical lymphocytes with cerebriform nuclei • Type C • Nodules of CD30+ cells—histologically indistinguishable from CD30+ ALCL

Lymphomatoid Papulosis

Type A:

Large atypical CD30+ cells in a mixed background of neutrophils, eosinophils, histiocytes and lymphocytes

Lymphomatoid Papulosis

Type B: “MF-like”

From: El Shabrawi-Caelen et al. Arch Dermatol 2004:140:441-7

92 Lymphomatoid Papulosis Type C: Histologically indistinguishable from CD30+ ALCL

Lymphomatoid Papulosis • Immunophenotypic Profile • Activated helper cells • CD30+ • CD4+ (less than 5% of cases CD8+) • Variable loss of CD2, CD3, or CD5 • Cytotoxic protein expression (TIA-1, granzyme) • Alk-1- • CD15-

Lymphomatoid Papulosis

• Differential Diagnosis • Type A • Reactive CD30+ proliferations (arthropod bite, , drug eruptions) Cepeda et al. Am J Surg Pathol. 2003:27:91 • Type B • Mycosis Fungoides • Pityriasis lichenoides (PLEVA)

93 Mycosis fungoides

• Persistent patches and plaques • Not papules

Mycosis Fungoides

• Histologic Features • Upper dermal band-like lymphocytic infiltrate • Variable epidermal changes (parakeratosis) • Halo perinuclear effect with minimal spongiosis • Epidermotropism • Nuclear atypia

Lymphomatoid Papulosis

• Type C • Mycosis fungoides with large cell transformation • Primary cutaneous CD30+ lymphoma (ALCL)

94 ALCL • Clinical • Can present at any age with one or multiple often ulcerated nodules • Three categories • Primary cutaneous – excellent prognosis • Secondary arising in background of pre-existent MF or LYP. Large cell transformation of MF carries a poor prognosis • Cutaneous spread from systemic CD30+ lymphoma

CD 30

LYP vs. ALCL

FEATURE LYP CD30+ ALCL No. of Lesions Numerous Solitary or few Usually limited to Distribution Limbs & abdomen one region Size of Lesions 1.0 cm or less Usually >1.0 cm Regression Invariable Uncommon Configuration Wedge-shaped or Nodular and of Infiltrate nodular/diffuse diffuse CD30+ Cells Scattered Confluent sheet Background Typical, often Less common, at Inflammation admixture periphery Necrosis Absent Present

95 Type D lymphomatoid papulosis

• Newly described variant • Clinically similar to LYP with waxing and waning papules • Microscopically resembles cutaneous aggressive CD8-positive cytotoxic T-cell lymphoma • Prominent epidermotropism • CD8+, CD30+

Type E Lymphomatoid Papulosis

Lymphomatoid Papulosis

• Practical Tips • Clinical correlation is paramount for correct diagnosis • Without knowledge of the clinical presentation, cannot be definitive • Often best signed out as ―CD30 positive lymphoproliferative disorder, see comment‖ • Comment: ―If there are multiple papules, the histologic features would be consistent with lymphomatoid papulosis‖ • Be aware of mimics in the differential diagnosis!

96 Case

70 year-old man with chronic lymphocytic leukemia presents with vesiculobullous lesion

97 Arthropod Bite Reaction

• Clinical • Variable • Erythematous pruritic or multiple papules • Microscopic • Epidermis may show acute necrosis or may look normal • Papillary dermal edema • Wedge-shaped superficial and deep perivascular and interstitial infiltrate of eosinophils and mononuclear cells

98 Arthropod Bite Reaction

• Differential Diagnosis • PLEVA • Lymphomatoid papulosis • Non-specific dermal hypersensitivity reaction • Urticaria • Drug reaction

Arthropod Bite Reaction • Clinical • Variable • Erythematous pruritic papule or multiple papules • Microscopic • Epidermis may show acute necrosis • Papillary dermal edema • Wedge-shaped superficial and deep perivascular and interstitial infiltrate of eosinophils and mononuclear cells

Practical Tips

• Diagnosis = Superficial and deep perivascular mixed cell infiltrate or Dermal hypersensitivity reaction, see note • Note: The histologic features are compatible with a dermal hypersensitivity reaction. The differential would include an arthropod bite reaction. CPC recommended. • Patients with CLL may have prominent reactions • Less interface change than PLEVA • Flea bites often neutrophil-rich

99 Dermal Hypersensitivity Reaction

• Clinical • Variable • Microscopic • Superficial or superficial and deep perivascular infiltrate • Lymphocytes and some eosinophils • Differential Dx • Arthropod bite reaction, drug eruption, urticaria, fungal infection, papular eczema, etc • Tips • Wastebasket term • Include DDx in the note

Interstitial Patterns

• Nodular or diffuse infiltrates • Sweet‘s syndrome • Mastocytosis (previously discussed) • Sarcoidosis • Cutaneous lymphoid hyperplasia • Palisading granulomatous dermatitis • •

Nodular or Diffuse Infiltrates

• Significant overlap with superficial and deep perivascular pattern • More interstitial inflammation • Can be sheet-like (diffuse) or aggregated (nodular)

100 Case

3 year-old boy with abrupt onset of painful erythematous plaques and nodules

101 102 Neutrophilic Dermatosis (Sweet‘s Syndrome) • Clinical • Diffuse violaceous tender nodules or plaques • May be associated with infections, myeloproliferative disorders, treatment with granulocyte colony-stimulating factors

Sweet‘s Syndrome

• Microscopic • No or minimal epidermal change • Dense infiltrate of neutrophils in reticular dermis • Leukocytoclasis but no true vasculitis

103 Sweet‘s Syndrome

• Differential Diagnosis • Leukocytoclastic vasculitis • Bowel bypass syndrome • Rheumatoid neutrophilic dermatosis • Pyoderma gangrenosum • Granuloma faciale

Pyoderma Gangrenosum

Infiltrate is similar but Sweet‘s does not have ulceration

104 Granuloma Faciale

• Clinical features • Adults • M>F • Asymptomatic red- brown plaques on cheeks

Granuloma Faciale

105 Sweet‘s Syndrome

• Practical Tips • No true vasculitis • Ulceration uncommon in Sweet‘s • Eosinophils are uncommon in Sweet‘s • ―neutrophilic dermatosis, see comment‖ ―The histologic features are consistent with Sweet‘s syndrome; if there is a clinical suspicion of an infectious etiology, tissue culture is recommended‖

Case

40 year-old woman with erythematous cutaneous nodule

106 107 Sarcoidosis

• Up to 35% may have cutaneous manifestations • Clinical manifestations variable • May indicate more severe disease • DDx: infection, sarcoidal variant of granuloma annulare, foreign body reaction

Practical Tips

• Dx: granulomatous dermatitis • Note: The histologic features are consistent with sarcoidosis in the appropriate clinical context • Diagnosis of exclusion • Consider special stains for microorganisms • May see sarcoidal reactions to foreign bodies

B-Cutaneous Lymphoid Hyperplasia (Lymphocytoma Cutis) • Clinical • Solitary nodule or plaque most commonly on head and neck • Can be associated with Borrelia infection • Microscopic • Top-heavy nodular to diffuse lymphocytic infiltrate admixed with eosinophils and plasma cells • Polarized germinal centers • Irregular germinal centers with tingible body macrophages • High Ki-67 labeling in germinal centers

108 109 B-Cutaneous Lymphoid Hyperplasia (Lymphocytoma Cutis) • Differential Diagnosis • Follicular center cell lymphoma • Marginal zone lymphoma • Tips • Approach with caution • Must exclude lymphoma (immunostains, clonality studies) • Dx: cutaneous lymphoid infiltrate consistent with reactive process, see note • Note: Continued clinical follow-up is recommended. If the lesion persists or progresses, additional biopsies may be helpful.

110 Palisading Granulomatous Dermatitis • Granuloma annulare • Necrobiosis lipoidica • Rheumatoid nodule

Case

23 year-old woman with asymptomatic annular lesions

111 Granuloma Annulare

• Clinical • Asymptomatic papules with annular configuration • Usually on extremities

112 Granuloma Annulare

• Microscopic • Most commonly involves upper and mid reticular dermis • Central zone of altered collagen fibers with associated dermal mucin surrounded by a palisade of histiocytes with some giant cells • Interstitial pattern common • Perivascular lymphocytic infiltrate with variable numbers of eosinophils • Neutrophils may be prominent early • Rarely may resemble sarcoidal granulomas • Rarely may be confined to the subcutis

113 114 Interstitial pattern of granuloma annulare

Deep granuloma annulare

115 Granuloma Annulare

• Differential Diagnosis • Necrobiosis lipoidica • Rheumatoid nodule • Granulomatous drug reaction • Sarcoidosis •

Practical Tips

• Palisade not always well developed • Low power examination • Altered collagen looks more ‗red‘ • Interstitial pattern common

Necrobiosis Lipoidica

• Clinical • Yellow, indurated plaques on lower legs • Small percentage (<5%) of patients have underlying diabetes mellitus • Microscopic • Affects entire dermis • Tiered arrangement of elongated zones of altered collagen (necrobiosis) separated by an interstitial infiltrate of histiocytes (resembles layer cake or bacon) • Multinucleated histiocytes common • Aggregates of lymphocytes and plasma cells

116 117 118 Practical Tips

• Low power examination • Tiers of altered collagen and histiocytes create layer cake or bacon look • Plasma cells favor necrobiosis lipoidica over GA • Most cases on legs • Ambiguous cases • Dx: palisading granulomatous dermatitis • Note: what you favor

Rheumatoid Nodule

Rheumatoid Nodule

• Microscopic • Lesions are located in the deep dermis, subcutaneous fat or soft tissue • Central areas of acellular fibrin surrounded by histiocytes and giant cells in a palisaded pattern • Lymphocytes, plasma cells and eosinophils may be present

119 Sclerosing Dermatoses

• Scleroderma/Morphea • Lichen sclerosus et atrophicus

120 Case

17 year-old boy with large, variably pigmented area of firm skin

121 Morphea

• Clinical • Also known as localized scleroderma • Localized indurated plaques, frequently on trunk • Microscopic • Indistinguishable from scleroderma

Scleroderma

• Clinical • Multisystem connective tissue disease • Two major clinical groups • Group 1: limited disease involving hands, forearms and face, often have CREST syndrome • Group 2: Diffuse cutaneous sclerosis and frequent visceral involvement • Indurated skin, sclerodactyly, hypopigmentation with perifollicular pigment retention,

122 Scleroderma/Morphea

• Microscopic • Thickened, hyalinized and compacted collagen fibers • Variable perivascular lymphoplasmacytic infiltrate • Differential Diagnosis • Morphea, scleroderma, sclerodermoid graft vs. host disease, scar, normal skin from back

123 Practical Tips

• ―Square‖ punch biopsy • Normally punch biopsies have a tapered appearance • Edges of biopsy are parallel in morphea • Differentiate from normal back • Decreased spaces between collagen fibers • Entrapped adnexal structures

124 Nephrogenic systemic fibrosis Review • Nephrogenic systemic fibrosis (NSF) • Nephrogenic fibrosing dermopathy (NFD) • Systemic disorder with most prominent effects in the skin • No cases identified prior to early 1997 • Cowper SE et al described first patients in 2000 • Scleromyxoedema-like cutaneous disease in renal- dialysis patients • Occurs only in people with kidney disease. • Not related to disease duration or underlying cause

Nephrogenic systemic fibrosis Clinical findings • Indurated papules and plaques, brawny thickening of skin • Lower extremities 97% • Upper extremities 77% • Face is usually spared • Systemic involvement • Joints and tendons • Muscles and peripheral nerves • Cardiovascular • Pulmonary

Jimenez SA, Arlett CM, Sandorfi N et al. Arthritis Rheum 2003; 50: 2660-66

Role of Gadolinium (GD) • Relationship between Gd-containing contrast agents and NSF noted in 2006 • Grobner et al, Nephrol Dial Transplant 2006;12(4):1104 • Gd deposition in skin has been recently demonstrated • Thakral and Abraham, J. Cutan Pathol 2009:36:1244-1254 • Pathogenesis--complex • Gd chelate is displaced by other cations (transmetallation) • TOXIC gd precipitates with anions as insoluble tissue deposits • Gd-deposition promotes fibrosis (? Factors)

125 CD 34 Procollagen

Lichen Sclerosus

• Clinical • White papules and plaques, frequently with fine, crinkly scale • Predilection for genital area (also called balanitis xerotica obliterans on penis) • Microscopic • Atrophic epidermis with loss of normal rete peg pattern • Basal vacuolization (early lesions) • Edematous and homogenized papillary dermis • Variable lichenoid lymphocytic infiltrate beneath altered collagen

126 Lichen Sclerosus

Early lichen sclerosus is an interface dermatitis

127 Lichen Sclerosus

• Differential Diagnosis • Morphea • Lupus erythematosus • Practical Tips • Homogenization of dermis most important feature • Sometimes clinical and histologic overlap with morphea • Early lesions have interface change with overlap with lichen planus • DX: Lichenoid interface dermatitis, see comment • Comment: This could represent early lichen sclerosus or lichen planus.

Lichen Sclerosus • Practical tips • Consider possibility of early lichen sclerosus in any interface dermatitis of genital skin • Inflammatory lesions of LS may mimic MF! • Remember that lichen sclerosus may occur outside the anogenital area • Cases with histologic overlap with morphea: use descriptive diagnosis ―fibrosing dermatitis‖

Panniculitis

• Septal vs. lobular •  Nodular Vasculitis (Erythema Induratum)  Lipodermatosclerosis (Lipomembranous Panniculitis, Sclerosing Panniculitis)

128 Case

30 year-old woman with painful nodules on shins

129 130 Erythema Nodosum

• Clinical • Most common form of panniculitis • Acute onset of tender, erythematous nodules • Shins most common site, often bilateral • Subcutaneous hypersensitivity reaction that may be idiopathic or associated with infection (e.g. group A β-hemolytic streptococcus) or drugs (e.g. sulfa drugs, oral contraceptives)

Erythema Nodosum

• Microscopic • Widened septae with edema, inflammation, and later fibrosis • Lymphocytes, histiocytes and some neutrophils • Small granulomas • Lobular inflammation at periphery of subcutaneous fat lobule

131 Erythema Nodosum

• Differential Diagnosis • Infection • Trauma • Erythema induratum • Superficial migratory thrombophlebitis • Lipodermatosclerosis • Lupus panniculitis • Subcutaneous morphea

Nodular Vasculitis (Erythema Induratum) • Clinical • Chronic, recurring tender nodules on lower legs • Calves most common site, often bilateral • Subcutaneous hypersensitivity reaction that in some patients is a reaction to underlying infection with M. tuberculosis

132 Nodular Vasculitis (Erythema Induratum) • Microscopic • Acute vasculitis in septae affecting artery and/or veins • Adjacent lobular panniculitis with granulomas and fat necrosis • Septae may be widened in older lesions

133 Nodular Vasculitis (Erythema Induratum) • Differential Diagnosis • Erythema nodosum • Infection • Polyarteritis nodosa • Thrombophlebitis • Lupus panniculitis

Lipodermatosclerosis

• Clinical • Usually bilateral indurated plaques on medial aspects of lower legs • Associated with stasis changes secondary to venous insufficiency and obesity

134 Lipodermatosclerosis

• Microscopic • Widened septae • Membranocystic fat necrosis • Cystic cavities lined by a crenulated, hyaline membrane • Mild perivascular lymphocytic infiltrate • Overlying features of stasis change in dermis and epidermis

Lipodermatosclerosis

• Differential Diagnosis • Erythema nodosum • Lupus panniculitis • Subcutaneous morphea

135 Panniculitis

• Primary patterns • Septal: inflammation centered in septum • Lobular: inflammation primarily in lobules • Tips: • Almost all cases will show both septal and lobular inflammation • Look for predominant pattern

Immunobullous Disease

• Intraepidermal blister • Pemphigus • Subepidermal blister • Bullous pemphigoid •

136 Pemphigus Vulgaris

• Clinical • Presents in the 4th-6th decades, M=F • Autoimmune blistering disease • Oral involvement common • IgG against desmoglein 3 in desmosomes • Desmosomes hold epithelial cells together

137 Pemphigus

• Microscopic • • Intraepidermal bullae • Basal layer spared (―Tombstone‖ layer) • Eosniophilic spongiosis • Mixed infiltrate with eosinophils • DIF: IgG and C3 around keratinocytes • Differential Diagnosis • Grover‘s disease, Hailey-Hailey disease

138 139 Grover‘s disease (transient acantholytic dermatosis)

• M>F, usually in winter • Pruritic papules and vesicles • Etiology unknown, but associated with sun exposure, sweating, radiation exposure • Acantholysis resembles pemphigus, but with corps ronds and corps grains (Darier disease-like) • May have spongiosis • DIF negative

Bullous Pemphigoid

• Clinical • Clinical overlap with pemphigus and sometimes contact dermatitis • Generally affects elderly patients • Bullae on extremities, intertriginous areas, abdomen and oral mucosa (1/3 pts) • Autoimmune disease • IgG against hemidesmosome proteins • Hemidesmosomes bind epidermis to basement membrane

140 Bullous Pemphigoid

• Microscopic • Subepidermal bullae • Mixed cell infiltrate with eosinophils • Linear IgG and C3 deposition • Eosinophilic spongiosis • Urticarial/prebullous phase • Differential Diagnosis • Epidermolysis bullosa acquisita,linear IgA bullous dermatosis, herpes gestationis, dermatitis herpetiformis

Dermatitis Herpetiformis

• Clinical • 3rd and 4th decades, M>F • Pruritic, burning vesicles, especially on extensor surfaces of extremities • Can resemble herpes or even a contact dermatitis • Associated with celiac disease • Responds to gluten free diet • IgA against basement membrane anchoring fibrils

141 Dermatitis Herpetiformis

• Microscopic • Subepidermal blister • Neutrophilic microabscesses • Neutrophil-rich infiltrate • Differential Diagnosis • Cicatricial pemphigoid, linear IgA

142 Practical Tips

• May not be possible to give specific diagnosis • Descriptive diagnosis • Note: A perilesional biopsy submitted in Michel‘s solution for direct immunofluorescence studies may help confirm the diagnosis.

Common Inflammatory Lesions Mimicking Tumors

143 Case

50 year-old man with lesion on face. Rule out BCC

144

• Clinical • Primarily affects adults • Central face • Telangiectasia • Papulo-pustular lesions • Erythematous nodules • May clinically resemble basal cell carcinoma

Rosacea

• Microscopic • Variable • Perivascular and perifollicular lymphohistiocytic infiltrate • May be granulomatous • Tips • If BCC in clinical DDx, get additional levels • Rosacea usually on central face

Case

70 year-old man with crusted lesion on ear. Rule out SCC

145 146 Chondrodermatitis Nodularis Helicis (CNCH) • Clinical • Older patients • Crusted to ulcerated lesion on helix • On ―sleeping side‖ • Essentially a small pressure • Clinically mimics squamous cell carcinoma or basal cell carcinoma

CNCH

• Microscopic • Ulcer • Reactive epidermal hyperplasia • Fibrinoid degeneration of dermis • Proliferation of perichondrial fibroblasts • Tips • High index of suspicion fromk ear lesions • Fibrinoid change • Absence of atypia

147 148