Histopathology (Rapini) Flashcards
Eczema
Focal parakeratosis (sometimes with crusting)
Neutrophils in the stratum corneum if secondarily impetigniginised
Acanthosis or hyperkeratosis (sometimes)
Spongiosis, sometimes spongiotic vesicles
Superficial perivascular lymphocytes, occasional eosinophils
Lichen simplex chronicus
Hyperkeratosis with focal parakeratosis
Hypergranulosis Impressive irregular acanthosis
Vertical orientation of collagen in dermal papillae
Perivascular lymphocytic infiltrate
Prominent fibroblasts (sometimes)
Multinucleated fibroblasts (Montgomery giant cells) (occasionally)
Enlarged nerves (occasionally)
Pityriasis rosea
SAMPLER
Spongiosis
Acanthosis
Mounds of parakeratosis
Perivascular Lymphocytes
Extravasated Red blood cells
Lichen striatus
Focal parakeratosis
Mild acanthosis (psoriasiform sometimes)
Spongiosis
Dyskeratotic keratinocytes (sometimes)
Focal basal layer liquefaction (sometimes)
Perivascular or lichenoid lymphocytes (often with inflammation around follicles / around sweat ducts)
Pityriasis alba
Focal parakeratosis Focal spongiosis Perivascular lymphocytes
Flegel’s disease (hyperkeratosis lenticularis perstans)
Localised hyperkeratotic mound with parakeratosis
Hypogranulosis
Atrophy of the spinous layer
Lichenoid lymphocytes
Psoriasis
Confluent parakeratosis
Hyperkeratosis
Neutrophils in stratum corneum (Munro micro abscesses) and spinous layer (spongiform pustules of Kogoj)
Hypogranulosis
Suprapapillary thinning of the epidermis
Regular acanthosis with clubbed rete ridges
Dilated capillaries in dermal papillae
Perivascular lymphocytes
Parapsoriasis
Focal parakeratosis
Acanthosis sometimes, atrophy of epidermis sometimes
Spongiosis sometimes
Focal liquefaction of the basal layer sometimes
Perivascular/sometimes lichenoid lymphocytes
Erythrocyte extravasation sometimes
Pityriasis rubra pilaris
Follicular plugging (often)
Shoulder parakeratosis adjacent to follicular plugs
Checkerboard parakeratosis alternated with orthokeratosis
Irregular acanthosis, often psoriasiform
Acantholysis, focal, sometimes
Perivascular lymphocytes, occasionally lichenoid
Lichen planus
Compact hyperkeratosis (usually no parakeratosis unless rubbed/oral)
Hypergranulosis (often wedge-shaped)
Irregular acanthosis with saw-toothed rate ridges
Colloid bodies (often)
Liquefaction degeneration of the basal layer
Lichenoid lymphocytes in the papillary dermis
Melanin incontinence (often)
DIF findings: IgM and fibrin staining colloid bodies
Lichen nitidus
Epidermal atrophy
Parakeratosis (often)
Focal ball of papillary dermal lymphocytes with epidermal rete ridges form a collarette “Ball in clutch”
Multinucleated giant cells (sometimes)
Focal liquefaction degeneration of the basal layer
Keratosis lichenoides chronica (Nekam disease)
Focal parakeratosis
Epidermis acanthotic or atrophic
Liquefaction degeneration of the basal layer
Lichenoid lymphocytes
PLEVA/PLC
Focal parakeratosis, often with scale crust
Dense wedge-shaped infiltrate centered upon basal layer zone of the papule with prominent lymphocytic exocytosis into the epidermis
Necrotic keratinocytes (often)
Spongiosis (with intraepidermal vesicles sometimes)
Liquefaction degeneration of the basal layer
Extravasation of erythrocytes, often in the epidermis
Palmoplantar keratoderma
Prominent hyperkeratosis, hypergranulosis, acanthosis
Sparse perivascular lymphocytes
Urticaria
Epidermis normal
Dermal oedema
Sparse perivascular and interstitial eosinophils, lymphocytes, neutrophils, and/or mast cells
Erythema multiforme
Necrotic keratinocytes
Spongiosis (sometimes), rarely intraepidermal vesicles
Basal layer liquefaction (sometimes subepidermal blister)
Oedema of the papillary dermis
Perivascular or interface lymphocytes, rarely with eosinophils
Extravasated erythrocytes (sometimes)
Erythema annulare centrifugum
Focal spongiosis or parakeratosis (occasionally)
Sharply demarcated ‘coat-sleeve’ lymphocytes densely arranged around dilated superficial and deep blood vessels
Erythema gyratum repens
(non-specific) Mild focal spongiosis and parakeratosis
Perivascular lymphocytes, sometimes with eosinophils
Drug eruption
Drug reactions in the skin can produce almost any clinical and histologic pattern
Polymorphous eruption of pregnancy / Pruritic urticarial papules and plaques of pregnancy
Mild focal parakeratosis and spongiosis
Oedema of dermis
Perivascular lymphocytes with eosinophils
Negative DIF for immunoglobulins/complements
Sweet syndrome
Variable epidermal change (sometimes necrosis)
Superficial dermal oedema, sometimes sub epidermal blister
Diffuse dermal neutrophils, lymphocytes, histiocytes, few eosinophils
No true vasculitis, but nuclear dust common
Extravasated erythrocytes (sometimes)
Well syndrome
Intraepidermal or sub epidermal blisters (sometimes)
Diffuse dermal eosinophils, lymphocytes, histiocytes
Flame figures in the dermis
Erythema ab igne
Epidermal atrophy (sometimes)
Keratinocyte atypia (sometimes)
Liquefaction degeneration of the basal layer, focal (sometimes)
Dilated dermal blood vessels
Elastosis in the dermis
Melanin incontinence and haemosiderin in the dermis
Livedo reticular and cutis marmarata
Vascular dilation or normal appearance on biopsy
Sparse or no inflammation
Not a true vasculitis
Erythema dyschromicum perstans / ashy dermatosis
Liquefaction degeneration of the basal layer, colloid bodies, mild or absent
Melanin incontinence
Perivascular or interface lymphocytes (sparse, early lesions only)
Chilblains / perniosis
Epidermis normal, rarely necrotic/ulcerated
Dermal oedema (often)
Perivascular lymphocytes (sometimes around sweat ducts)
Thrombi sometimes
Erythromelalgia
Mild vascular dilation with thickened basement membrane and endothelial swelling
Arteriolar thrombi (sometimes)
Perivascular dermal oedema
Sparse perivascular lymphocytes
Leukocytoclastic vasculitis
Epidermis variable: normal, necrotic, vesicular, pustular
Vasculitis of small venues with predominant number of neutrophils, sometimes eosinophils, lymphocytes or histiocytes
Nuclear dust often
Red blood cell extravasation often
Thrombi sometimes
DIF: IgG, IgM, complement in granular pattern in the superficial blood vessels
Fibrin deposits in young or old lesions
Granuloma faciale
Epidermis unremarkable
Grenz zone above a diffuse mixed dermal neutrophils, eosinophils, lymphocytes, histiocytes (sometimes plasma or mast cells)
Leukocytoclastic vasculitis
Haemosiderin in dermis
Erythema elevatum diutinum
Epidermis unremarkable
Leukocytoclastic vasculitis (less apparent in older lesions)
Fibrosis or lipid deposits in older lesions
Polyarteritis nodosa
Epidermis normal, necrotic, or ulcerated
Leukocytoclastic vasculitis of small to medium arteries of deep dermis or subcutaneous fat
Intimal proliferation and thrombi sometimes
Fibrosis in older lesions
Eosinophilic granulomatosis with polyangiitis
Epidermis normal, necrotic, or ulcerated
Neutrophilic vasculitis of small vessels
Many eosinophils in the dermis
Granulomatous inflammation and necrosis within blood vessels and in surrounding dermis and subcutaneous tissue, often palisading
Thrombi or extravasated erythrocytes sometimes
Granulomatosis with polyangiitis
Epidermis often necrotic or ulcerated
Non-specific perivascular inflammation
Vasculitis of small arteries and veins involving neutrophils, lymphocytes, plasma cells and (rarely) eosinophils
Granulomatous inflammation in blood vessels and in surrounding dermis often, sometimes palisading
Thrombi often, resulting in extensive necrosis
Extravasation of erythrocytes
Purpura pigmentosa chronica
Epidermis normal, sometimes spongiosis of focal parakeratosis
Extravasated erythrocytes, endothelial swelling, perivascular lymphocytes
Haemosiderin in older lesions
Cryoglobulinemia (Type 1)
Epidermis normal, necrotic or ulcerated
Thrombi and precipitated cryoglobulin in dermal blood vessels
Extravasated erythrocytes
Sparse perivascular lymphocytes sometimes (not a true vasculitis)
Degos disease / Malignant atrophic papulosis
Atrophic epidermis in old lesions (sometimes with hyperkeratosis)
Wedge-shaped dermal infarct with broad base toward epidermis
Necrotic or absent adnexal structures
Mucin in dermis in early red macule, or around edges of early white papules, sclerosis in older lesions
Thrombosed arteriole (usually S/C fat) with minimal inflammation, endothelial swelling, or intimal fibrosis
Behçet syndrome
Epidermis with ulceration or pustule formation
Diffuse dermal neutrophils, lymphocytes, and/or histiocytes, sometimes with vasculitis
Pyoderma gangrenosum
Epidermis necrotic, or ulcerated, occasionally with pustules
Pseudoepitheliomatous hyperplasia at the edge of ulcer (sometimes)
Diffuse infiltrate of neutrophils, lymphocytes, and histiocytes in the dermis (sometimes with vasculitis)
Atrophie blanche / Livedoid vasculopathy
Atrophic, necrotic, or ulcerated epidermis
Hyalinised dermal blood vessel walls prominent
Thrombi often Extravasation of erythrocytes
Dermal fibrosis in older lesions
Sparse perivascular lymphocytes or neutrophils (since inflammation is minimal)
DIF of perilesional skin reveals homogenous deposits of immunoglobulins, complement and fibrin in dermal blood vessels
Coagulopathies
Epidermis is normal or necrotic
Subepidermal blister sometimes
Thrombi in dermal blood vessels, dermal necrosis in late-stage lesions
Extravasated erythrocytes in the dermis
Little or no inflammation
Solar purpura
Atrophic epidermis (sometimes)
Solar elastosis
Extravasated erythrocytes in the dermis
No inflammation
Scurvy
Follicular plugging
Perifollicular erythrocyte extravasation
Mild to absent perifollicular lymphocytic infiltrate
Haemosiderin in older lesions
Warfarin necrosis
Epidermal necrosis
Subepidermal blister (sometimes)
Thrombi in dermal blood vessels, dermal necrosis
Sparse or no inflammation
Extravasation of erythrocytes in the dermis
Buerger’s disease
Thrombi of medium sized arteries with occlusion of lumina
Ischaemia, necrosis, ulcers
Mixed inflammatory cells in vessel walls
Acropustulosis of infancy
Subcorneal pustule of neutrophils
Perivascular neutrophils and lymphocytes
Transient neonatal pustular melanosis
Subcorneal pustule, sometimes with eosinophils and neutrophils
Perivascular neutrophils, lymphocytes, and eosinophils
Erythema toxic neonatorum
Subcorneal vesicle often centred upon a hair follicle, containing mostly eosinophils
Perivascular infiltrate of mostly eosinophils
Pemphigus
Acantholysis in the epidermis (suprabasal for PV, superficial for PF)
None/few necrotic keratinocytes
Perivascular lymphocytes, eosinophils, sometimes neutrophils or plasma cells
Direct immunofluorescence with IgG and complement within intercellular spaces
Hailey-hailey disease
Extensive acantholysis through the epidermis (dilapidated brick wall)
Dyskeratotic keratinocytes (sometimes)
Perivascular lymphocytes, eosinophils absent or rare
DIF for immunoglobulins and complement negative
Grover disease
Small foci of acantholysis, usually suprabasal
Dyskeratotic cells (acantholytic dyskeratosis)
Spongiosis (sometimes)
Perivascular lymphocytes (sometimes eosinophils)
DIF for immunoglobulins and complement negative
Friction blister
Blister in superficial epidermis (near granular layer)
Degenerated keratinocytes adjacent to blister
Inflammation mild or absent
Bullous pemphigoid
Eosinophilic spongiosis (sometimes, especially in early non-blistered red plaques)
Subepidermal blister
Viable roof over blister, necrotic in old blisters
Perivascular lymphocytes and eosinophils, sometimes very sparse (cell-poor pemphigoid)
Superficial dermal oedema
Microabscesses of neutrophils, eosinophils in the dermal papillae (sometimes)
DIF linear IgG (IgG4) and complement deposits in the BMZ (usually roof)
Mucous membrane pemphigoid
Subepidermal blister seen in some cases or sometimes squamous metaplasia only
Viable or eroded roof over the blister
Perivascular lymphocytes with variable eosinophils, neutrophils, or plasma cells, if on mucous membrane
DIF linear IgG (IgG4) and complement deposits in the BMZ (usually roof)
Pemphigoid gestationis
Spongiosis, sometimes eosinophilic spongiosis, or intraepidermal vesicle
Necrotic keratinocyte sometimes (especially basal layer)
Marked papillary dermal oedema, subepidermal blister
Perivascular lymphocytes with eosinophils DIF linear IgG (IgG4) and complement deposits in the BMZ (usually roof) (complement > IgG)
Linear IgA bullous dermatosis
Subepidermal blister
Sometimes microabscesses of neutrophils in the dermal papillae
Perivascular lymphocytes, eosinophils (sometimes)
DIF: linear staining of IgA (less often with IgG, IgM or c4)
Dermatitis herpetiformis
Neutrophilic micro abscesses in the dermal papillae, few eosinophils
Small subepidermal vesicles
DIF: granular deposits of IgA in the tips of the dermal papillae
Epidermolysis bullosa
Subepidermal blister
Sparse (cell-poor) perivascular lymphocytes
Type IV collagen immunohistochemical staining
DIF negative except in acquisita (linear IgG and complement in the dermal epidermal junction)
Burns
Epidermal necrosis depending on severity
Elongated nuclei of keratinocytes in electrical burns
Subepidermal blisters
Dermal necrosis
No inflammation until lesion becomes older
Ischaemic bullae
Epidermal necrosis (often)
Intra- or more commonly subepidermal bulla
Necrosis of adnexa (esp sweat ducts)
Dermal necrosis (sometimes)
Minimal inflammation except sparse neutrophils in areas of necrosis
Negative DIF
Bullosis diabeticorum
Blister varies from sub corneal, intraepidermal to subepidermal
Inflammation sparse
Negative DIF
Granuloma annulare
Epidermis normal
Palisading granulomas around small foci of mild connective tissue degeneration (necrobiosis) and mucin accumulation
Single-filing/subtle interstitial pattern of histiocytes between collagen bundles
Perivascular lymphocytes (often), sometimes neutrophils or eosinophils are present
Necrobiosis lipoidica
Epidermal normal, or atrophic, sometimes ulceration
Necrobiotic collagen, often with sclerosis, with palisading granulomas in the dermis often oriented parallel to the epidermis (resembling a layered cake or lasagna)
Dermal interstitial infiltrate consists of histiocytes, many multinucleated giant cells, lymphocytes, plasma cells
Rheumatoid nodule
Palisading granuloma around degenerated connective tissue and fibrin in the deposit deep dermis or subcutaneous tissue
Histiocytes and lymphocytes mainly, only a few multinucleated giant cells
Actinic granuloma of O’Brien
Nodular or diffuse granulomatous infiltrate of lymphocytes, histiocytes and many multinucleated giant cells containing asteroid bodies and elastic tissue (elastic fibre phagocytosis)
Usually no necrobiosis and mucin, and less palisading than GA
Three zones in well-developed lesions: solar elastosis, granuloma with elastic fibre phagocytosis, and zone of absent elastic fibres)
Sarcoidosis
Epidermis normal, sometimes parakeratosis, hyperkeratosis or acanthosis, such as in the ichthyotic variant
Non-caseating (rarely caseating) well-demarcated granulomas in the dermis or subcutaneous tissue, often but not always “Naked” with few lymphoid cells around the epithelioid cells
Schauman bodies (round, blue, calcified, laminated inclusions) or asteroid bodies (stellate, intracytoplasmic eosinophilic inclusions) sometimes present within multinucleated giant cells (not specific for sarcoidosis)
Foreign body granuloma
Caseating or non-caseating granulomas with foreign material
Fibrosis or sclerosis replaces granulomas in older lesions
Cheilitis granulomotasa / orofacial granulomatosis
Epidermis/mucosa normal
Interstitial or nodular infiltrate of lymphocytes and plasma cells in an oedematous stroma
Tuberculoid granulomas sometimes subtle, not always present, may impinge upon adjacent dilated blood vessels and lymphatics
Multicentric reticulohistiocytosis
Nodular infiltrate of large true histiocytes with abundant eosinophilic non-foamy “ground glass” cytoplasm, and positive histiocytic stains
Bizarre multinucleated giant cells, often polygonal, with irregular distributed nuclei in older lesions
Mixed diffuse infiltrate of lymphocytes, and sometimes neutrophils or eosinophils
Xanthoma
Foam cells in dermis (positive for lipid with special stains such as oil-red-O)
Touton giant cells (sometimes)
Small numbers of lymphocytes or neutrophils in younger lesions (especially eruptive)
Fibrosis or cholesterol clefts in older lesions
Juvenile xanthogranuloma
Nodular or diffuse mixed infiltrate of histiocytes, lymphocytes, and eosinophils (eosinophils more common in younger lesions)
Foamy histiocytes and Toulon giant cells in older lesions
Fibrosis prominent in older lesions
Positive staining with CD68, CD163, HAM56, factor XIIIa (dermal dendrocytes)
Necrobiotic xanthogranuloma
Palisading granulomas with areas of necrosis (more severe degeneration than the necrobiosis seen with GA/NLD)
Cholesterol clefts common
Foamy histiocytes, touton giant cells, foreign body giant cells, lymphocytes, plasma cells, neutrophils
Verruciform xanthoma
Hyperkeratosis, acanthosis, papillomatosis (verrucous)
Foamy histiocytes limited to submucosal or dermal papillae
Porphyria cutanea tarda
Subepidermal blister
Festooning of dermal papillae
Caterpillar bodies (eosinophilic, linear, segmented basement membrane material resembling dyskeratotic cells, sometimes found at the roof of the blister)
Sparse hyalinised material around blood vessels
Dermal sclerosis in late stage
DIF: IgG and C3 around papillary dermal vessels with lesser staining at DEJ in the lamina lucida
Colloid milium
Often epidermal atrophy with hyperkeratosis
Nodular fissured masses of amorphous eosinophilic material in the superficial dermis
Separation between the masses by a thin rim of collagen, elastic tissue, or collarette of epidermal rete ridges
Special stains of the eosinophilic material (Congo red and crystal violet) often stain positive as in amyloidosis
Solar elastosis common
Lipoid proteinosis
Hyperkeratosis, papillomatosis (sometimes)
Amorphous eosinophilic deposits beginning around the vessels, later diffuse throughout the dermis, with a tendency to be perpendicular to the epidermis and to arrange around adnexal structures and blood vessels
Positive staining with colloidal iron, alcian blue, Sudan black, PAS with or without diastase
Weak amyloid staining
Amyloidosis
Deposits of amorphous, eosinophilic, fissured material
In systemic: especially around vessels/adnexal structures
Special stains positive: crystal violet, Congo red, thioflavin T, pagoda red 9, scarlet red, PAS moderately positive
Keratin stains such as EAB-903 may be positive in lichen/macular amyloidosis
Gout
Amorphous deposits of eosinophilic material in dermis and subcutaneous tissue with formalin-fixed tissue
Brownish, doubly refractive needle-shaped crystals in clefts if alcohol fixed, or in the deeper aspects of incompletely fixed/processed tissue
Lymphocytes, histiocytes, and multinucleated giant cells around the deposits
Positive staining with von Kossa, but de Galantha is more specific for urates
Pretibial myxoedema
Large spaces between collagen bundles apparent with H&E
Abundant acid mucopolysaccharide between collagen bundles of the dermis: Alcian blue, colloidal iron, or toluidine blue
Normal or slightly increased number of fibroblasts
Sometimes increased mast cells
Papular mucinosis
Circumscribed deposits of abundant acid mucopolysaccharide between collagen bundles in the superficial dermis, positive with alcian blue, colloidal iron, or toluidine blue stains
Fibrosis sometimes
Increased mast cells
Digital mucous cyst
Hyperplasia of epidermis sometimes
Localised increased mucin in clefts between collagen bundles or in a cystic space
Not true cyst, but collarette of epidermal rete ridges may clutch the cyst
Synovial lining (sometimes)
Positive staining with acid mucopolysaccharide stains
Mucocele
Rupture minor salivary duct or gland
One or several spaces filled with sialomyucin, lined by granulation tissue or a mixed infiltrate of fibroblasts, lymphocytes, and histiocytes
Sialomucin is positive for both neutral mucopolysaccharide (PAS, diastase resistant) and acid mucopolysaccharide
Focal mucinosis
Localised increased dermal mucin
Normal or slightly increased number of S100 negative fibroblasts
Positive staining with acid mucopolysaccharide stains (Alcian blue, toluidine blue, or colloidal blue)
Scleredema of Buschke
Dermis markedly thicker than normal, extending below sweat gland coils, with very thick collagen bundles separated by clefts
Normal or decrease number of fibroblasts Increase in acid mucopolysaccharide between collagen bundles (stains with Alcian blue, colloidal iron or toluidine blue)
Reticular erythematous mucinosis syndrome
Perivascular and perifollicular lymphocytes
Very subtle to moderate amount of mucin between collagen bundles
Mucin is positive with acid mucopolysaccharide stains (alcian blue, toluidine blue, sometimes mucicarmine)
Mucopolysaccharidoses
Granules within cytoplasm of fibroblasts or histiocytes (“gargoyle cells”) and occasionally within keratinocytes that can be stained with Giemsa, toluidine blue, Alcian blue, or colloidal iron
Cells may appear vacuolated prior to special stains Special fixation in alcohol may be needed Mucin in middle or deep dermis in papulonodules
Hurler’s syndrome (MPS I) AR
Hunter’s syndrome (MPS II) XLR
Calcinosis cutis
Dark, basophilic, brittle, often fractured deposits, sometimes surrounded by fibrosis or foreign body reaction
Positive staining with von Kossa or alizarin red (more specific for calcium)
Ochronosis
Yellow-brown “banana-shaped” deposits on homogenised collagen bundles
Small yellow-brown granules in endothelial cells and secretory portion of sweat glands
Few multinucleated giant cells (rarely)
Positive black staining with methylene blue or cresyl violet
Haemochromatosis
Increased melanin in basal layer
Haemosiderin deposits scattered through dermis, mainly around blood vessels and sweat glands (Perl’s stain best seen)
Argyria
Sometimes increased melanin in basal layer
Tiny black particles in the dermis, especially around sweat glands, hair follicles, blood vessels, elastic fibres
Nephrogenic systemic fibrosis
Fibrosis changes in dermis, sometime more subtle than the impressive clinical findings, often extending into deep subcutaneous tissue
Positive staining for CD34 and procollagen-1 (sometimes factor XIIIa positive)
Sometimes mucin increased between collagen bundles in dermis (positive for alcian blue or colloidal iron)
Usually no inflammation, but in some cases can be present
Gadolinium demonstrated in skin lesions with electron microscopy/X-ray spectroscopy
Solar elastosis
Amorphous, fibrous, or globular basophilic material in the dermis
Elastic fibres become bluish-grey and stain positively with elastic tissue stains
Acute radiodermatitis
Pale, vacuolated, or necrotic keratinocytes
Subepidermal blister, or ulceration sometimes
Superficial dermal oedema
Endothelial proliferation, vascular dilation, thrombi
Degeneration of dermal connective tissue
Chronic radiodermatitis
Epidermal hyperplasia, or atrophy, sometimes ulceration
Keratinocytes pale, atypical or necrotic
Telangiectatic blood vessels, sometimes surrounded by hyper plastic rete ridges
Thrombi sometimes
Decreased adnexal structures
Degenerated dermis (mainly hyalinised, sometimes basophilic)
Sometimes atypical, bizarre fibroblasts
Scleroderma
Epidermis normal or atrophic
Hyalinised dermis and subcutaneous fat, more prominent in late lesions
Sparse perivascular lymphocytes, sometimes plasma cells, in dermis or subcutaneous fat, more prominent in early lesions and in morphoea than in systemic sclerosis
Decreased adnexal structures, eccrine glands are entrapped by collagen and higher up in the dermis than usual because of increased collagen in subcutaneous fat
Atrophoderma of Pasini and Pierini
Hyalinised dermis, often subtle, requiring fusiform excision adjacent normal skin for comparison to appreciate the dermal atrophy in the involved skin
Perivascular lymphocytes in early lesions
Lichen sclerosus
Hyperkeratosis (often) but atrophy of spinous layer
Follicular plugging Liquefaction degeneration of the basal layer, rare sub-epidermal blister
Oedematous homogenised superificial dermis with vascular dilation
Lichenoid lymphocytes in early lesions (near basal layer in very early lesions, mid-dermis beneath homogenised zone later)
Vascular dilation
Progeria
Epidermal atrophy
Dermal fibrosis of sclerosis
Decreased adnexal structures
Decreased subcutaneous fat
Hutchinson-Gilford (childhood)
Werner’s syndrome (adult/teen)
Pachydermoperiostosis
Increased dense collagen and increased fibroblasts in the dermis
Increased acid mucopolysaccharide between collagen bundles
May have normal histology or dermal fibrosis with pilosebaceous hyperplasia
Pseudoxanthoma elasticum
Clumped, calcified elastic fibres in the dermis (positive staining for calcium on alizarin red or von Kossa stains, or for elastic tissue with Verhoeff stain)
Ehlers-Danlos syndrome
Normal appearing skin by light microscopy in most cases
Collagen fibres may have subtle thinning, with slight increase in elastic fibres
Dermal atrophy may be present
Pseudotumors at site of trauma show haemorrhage early, and fibrosis, multinucleated histiocytes and vascular proliferation late
Cutis laxa
Skin looks normal on H&E
Elastic stain shows decreased, thinned, degenerated, or nearly normal elastic fibres in the dermis
Lymphocytes, multinucleated giant cells rarely in dermis
Anetoderma
Normal epidermis Perivascular lymphocytes, histiocytes, neutrophils, or eosinophils Decreased or completely absent elastic tissue in the dermis with Verhoeff-van Gieson stain, but skin looks nearly normal with H&E
Kyrle’s disease
Hyperkeratotic plug containing degenerated material, sometimes associated with follicular orifices, sometimes completely perforating the epidermis or follicle, sometimes with neutrophils or crust
Parakeratosis and dyskeratotic keratinocytes
Epidermal hyperplasia around the plug
No increase in elastic fibres in the dermis and no elastic fibres or collagen fibres within the plug
Foreign body giant cells in the dermis at perforation sites (sometimes)
Elastosis perforans serpiginosa
Hyperkeratotic plug with transepidermal elimination of elastic fibres
Hyperplastic epidermis that often appears to clutch the dermis at the site of perforation (crab claw/vacuum cleaner)
Increased brightly eosinophilic elastic fibres in dermis near perforation (Verhoeff-van Gieson stain)
Bramble bush lumpy-bumpy elastic fibres with lateral buds in penicillamine-induced EPS
Macrophages, multinucleated giant cells, lymphocytes or neutrophils in the plug or dermis at site of perforation
Down syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome, PXE, Rothmund-Thomson syndrome, acrogeria
Reactive perforating collagenosis
Hyperkeratotic plug in the epidermis, often “perforating” through the epidermis
Transepidermal elimination of collagen fibres (red with Verhoeff-van Gieson stain) in the plug
Macrophages, multinucleated giant cells, lymphocytes, or neutrophils in the plug or dermis at site of perforation
Mid-dermal elastolysis
Normal-appearing skin with H&E
Mid-dermal loss of elastic fibres seen with Verhoeff-van Gieson stain
Macrophages with elastic fibre phagocytosis sometimes
Acne
Follicular plugging
Sometimes intraepidermal pustules overlying follicles or within follicles
Frequently ruptured pilosebaceous apparatus with perifollicular mixed infiltrate of neutrophils, lymphocytes, plasma cells, histiocytes, and/or multinucleated giant cells
Sometimes abscesses, sinus tracts, and fibrosis
Folliculitis
Perifollicular or intrafollicular mixed infiltrate of lymphocytes, histiocytes, or plasma cells, sometimes resulting in a ruptured follicle surrounded by neutrophils and multinucleated giant cells
Causative organisms may be present
Perifollicular fibrosis in older lesions
Perforating folliculitis
Follicular plugging
Perforation of the follicle by degenerating elastic and collagen fibres
Perifollicular neutrophils, lymphocytes or plasma cells
Trichostasis spinulosa
Numerous vellus hairs within a follicle
Keratosis pilaris
Follicular plugging
Sparse perifollicular lymphocytes or neutrophils sometimes
Miliaria
Crystallina: subcorneal vesicles with no inflammatory cells over sweat ducts
Rubra: spongiosis of intraepidermal sweat ducts sometimes producing intraepidermal vesicles, perivascular lymphocytes or neutrophils
Profunda: red nodules, or pustules, deeper and denser inflammation
Fox-Fordyce disease
Spongiosis or vesicle in plugged follicle near connection with apocrine duct
Perivascular or peri-sweat duct lymphocytes or neutrophils
Perifollicular foamy histiocytes
Follicular mucinosis
Acid mucopolysaccharide deposition (positive with Alcian blue or colloidal iron stains) in hair follicle between keratinocytes, resembling spongiosis
Perivascular or lichenoid lymphocytes, histiocytes or eosinophils with exocytosis into the follicles
Co-existing MF sometimes
Alopecia areata
Lymphocytes, sometimes eosinophils, around hair bulb lower portion of follicle in early lesions (swarm of bees)
Increased number of miniature (nanogen) telogen or catagen follicles or sometimes early anagen hair follicles in the superficial dermis
Fibrous tract remnants (follicular streamers) of destroyed follicles may be present
Pseudopelade of Brocq
Lymphocytes mainly around follicles in early lesions
Fibrosis and absent follicles in older lesions
Follicular trauma
Deformed hair shafts and follicles (trichomalacia)
Pigmented casts in follicles (blobs of melanin)
Empty follicles (hair shafts pulled out), with increased catagen or telogen follicles
Perifollicular lymphocytes, plasma cells, or neutrophils usually sparse or absent
Perifollicular haemorrhage (sometimes)
Perifollicular fibrosis, if follicle is destroyed, a vertical fibrous tract often remains
Androgenetic alopecia
Miniaturised vellus follicles in late stages
Increased telogen hairs in late stages
Vertical fibrous stelae of destroyed follicles may be present
Lipoedematous alopecia
Decreased follicles, increased telogen
Increased thickness of adipose tissue
Telogen effluvium
Increased telogen hair count
No miniaturised follicles
Neutrophilic eccrine hidradenitis
Neutrophils around eccrine sweat glands
No bacteria demonstrated
Syringosquamous metaplasia may occur in the chemotherapy-induced type
Ichthyosis
Compact hyperkeratosis
Normal or thickened granular layer in most variants (except ichthyosis vulgaris/acquired)
Varying degree of acanthosis, usually not much parakeratosis
Ichthyosis vulgaris
Compact orthokeratosis and acanthosis
Decreased or absent granular layer
Follicular plugging (sometimes)
Epidermolytic hyperkeratosis
Compact orthokeratosis and acanthosis
Hypergranulosis
Epidermolytic degeneration of keratinocytes
Intraepidermal blisters
Ectodermal dysplasia
Decreased number and hypoplasia of sebaceous glands and hair follicles
Decreased number or absent sweat glands in patients with anhidrotic form
Darier disease
Hyperkeratosis, parakeratosis sometimes, pseudoepitheliomatous hyperplasia sometimes, basaloid hyperplasia sometimes
Follicular plugging sometimes
Papillomatosis and acanthosis
Acantholytic dyskeratotic keratinocytes often forming corps roads and grains
Clefts or lacunae in suprabasal location due to acantholysis
Dyskeratosis congenita
Epidermis normal or atrophic
Melanin incontinence
Absent or minimal interface lymphocytes
Rothmund-thomson syndrome
Epidermal atrophy
Liquefaction degeneration of the basal layer in early lesions
Melanin incontinence
Perivascular or lichenoid lymphocytes in early lesions
Dilated blood vessels
RECQL4 (DNA Helicase gene)
Incontinentia pigmenti
First stage: eosinophilic spongiosis and intraepidermal vesicles containing eosinophils
Dyskeratotic keratinocytes
Perivascular lymphocytes and eosinophils
Second stage: Papillomatosis, hyperkeratosis and acanthosis
Pale glassy keratinocytes, often dyskeratotic, and forming squamous eddies
Minimal perivascular lymphocytes
Melanin incontinence
IKBKG (of NEMO complex)
Third stage: melanin incontinence with basal cell degeneration or basal cell hyperpigmentation
Hypomelanosis of Ito
Decreased melanocyte and melanin at the basal layer
Focal dermal hypoplasia / Goltz syndrome
Severe dermal atrophy so that the subcutaneous fat may reach the epidermis
PORCN gene
Albinism / Oculocutaneous
Melanocytes are present at the basal layer but do not actively produce melanin
Decreased or absent melanin demonstrated with Fontana melanin stain
Electron microscopy may detect immature or decreased melanosomes
Bloom syndrome
Interface dermatitis or perisvascular lymphocytic dermatitis
Telangiectasia
RECQ protein-like 3
Xeroderma pigmentosum
Epidermis may be atrophic or hyperkeratotic
Necrotic keratinocytes sometimes
Solar elastosis, telangiectasia
Basal layer decreased or increased melanin, dermal melanin incontinence
Perivascular lymphocytes
Ataxia-telangiectasia
Dilated blood vessels in the dermis
Cafe-au-lait macules (sometimes)
Impetigo
Subcorneal pustule filled with neutrophils and sometimes occasional acantholytic cells
Spongiosis often
Dermal perivascular lymphocytes and neutrophils
Gram-positive cocci sometimes found in pustule (culture more helpful)
Staphylococcus aureus and/or streptococcus pyogenes
Toxin-induced bacterial disease
Subcorneal blister containing only rarely inflammatory cells, and sometimes some acantholytic cells
Minimal or absent perisvascular neutrophils and lymphocytes
Bacteria not present in the blistering toxin-induced lesions
*Staphylococcus aureus (SSSS, TSS) Streptococcus pyogenes (Scarlet fever, rheumatic fever, TSS) Salmonelli typhi (Typhoid)*
Infectious cellulitis
Epidermis normal, sometimes with necrosis
Dermal oedema
Diffuse or interstitial infiltrate of predominantly neutrophils in the dermis (sometimes sparse)
Bacteria uncommonly can be seen with Gram stain
Culture of biopsy positive in less than 10% of cases
Streptococcus pyogenes, staphylococcus aureus, others
Anthrax
Epidermal necrosis or ulceration
Dermal oedema
Extravasated erythrocytes
Diffuse dermal neutrophils or minimal inflammation
Large gram-positive rods (1-8 microns) often visible with H&E
Bacillus anthracis
Tularaemia
Epidermal necrosis or ulceration
Mixed diffuse infiltrate of neutrophils, lymphocytes, histiocytes, and multinucleated giant cells
Granulomas may be tuberculoid or sarcoidal, sometimes with caseation
Gram-negative coccobacilli usually cannot be identified with special stains (Dieterle silver stain or fluorescent antibody stains may be helpful)
Frascisella Tularensis
Chancroid
Three zones of inflammation under an ulceration (not as specific as once thought)
Necrotic debris, fibrin, and neutrophils on the surface
Granulation tissue in the middle zone Lymphocytes, plasma cells deep
Gram-negative coccobacilli can rarely be demonstrated on Gram or Giemsa stains (best seen on smears)
Haemophilus ducreyi
Granuloma inguinale
Ulceration with granulation tissue
Pseudoepitheliomatous hyperplasia at the ulcer border (sometimes) 1.2 micron
Gram-negative organisms (Donovan bodies) sometimes within histiocytes with Giemsa or Warthin-Starry stains (best seen on smears)
Klebsiella granulomatis
Rhinoscleroma
Pseudoepitheliomatous hyperplasia sometimes in older lesions
Dense diffuse infiltrate of many plasma cells, Russell bodies, histiocytes, neutrophils and lymphocytes
Gram-negative rods (2-3 microns) seen within large vacuolated histiocytes (Mikulicz cells) with H&E stain, or better with Giemsa, PAS, Warthin-Starry, or immunostains
Marked fibrosis in older lesions
Klebsiella rhinoscleromatis
Atypical mycobacterial infection
Epidermis hyperplastic or ulcerated, sometimes with neutrophilic microabscesses
Diffuse dermal mixed infiltrate of neutrophils, histiocytes, and plasma cells
Tuberculoid granulomas often present, usually without caseation
Acid-fast bacilli found by AFB stain, culture, PCR Prominent fibrosis sometimes
Tuberculosis, leprae
Marinum, ulcerans, avium-intracellulare (AIDS)
Rapid growers: fortuitum, abscessus, chelonae
Lepromatous leprosy
Diffuse infiltrate of predominantly foamy histiocytes, separated from the epidermis by a Grenz zone
Acid-fast bacilli seen with Fite stain, sometime in clumps called globi
Tuberculoid leprosy
Tuberculoid granulomas that may reach the epidermis (no Grenz zone), with a tendency to be linear along cutaneous nerves and usually without caseation
Acid-fast bacilli rare, or not present with Fite stain
Mycobacterium leprae / lepromatosis
Primary syphilis
Ulceration of the epidermis
Diffuse infiltrate of many plasma cells, lymphocytes, histiocytes
Endothelial swelling and proliferation
Spirochetes often present with Within-Starry stain / or T. palladium immunostain
Treponema pallidum
Secondary syphilis
Epidermis may be normal, hyperkeratotic, psoriasiform, necrotic or ulcerated
Neutrophils or pustules may be in the epidermis
Perivascular or lichenoid infiltrate of many plasma cells, lymphocytes, and histiocytes.
Eosinophils occasionally present
Granulomatous infiltrate may be present in older lesions
Endothelial swelling and proliferation
Spirochetes present in epidermis or dermis in one-third of cases, best seen as epitheliotropic or vasculotropic on immunostain
Treponema pallidum
Tertiary syphilis
Epidermis normal, atrophic, hyperplastic, or ulcerated
Tuberculoid granulomas with or without caseation often with plasma cells
Endothelial swelling and proliferation
Spirochetes usually not identified with Warthin-Starry stain
Fibrosis in some lesions
Lyme disease
Sometime spongiosis
Perivascular lymphocytes and plasma cells or eosinophils
Spirochetes with silver stains (rarely found) or with molecular biologic techniques
Borrelia burgdorferi
Acrodermatitis chronica atrophicans
Epidermal atrophy
Periavascular or lichenoid lymphocytes, plasma cells, or eosinophils in early lesions
Dermal oedema in early lesions, severe dermal atrophy or sclerosis later
Decreased or absent adnexa in older lesions
Borrelia burgdorferi
Cat scratch disease
Perivascular or lichenoid infiltrate with lymphocytes, plasma cells, neutrophils or eosinophils, sometimes forming palisading granulomas
Bartonella henselae
Gonococcaemia
Pustules and epidermal necrosis, often
Septic neutrophilic vasculitis
Extravasated erythrocytes and thrombi Gram-negative diplococci seldom demonstrated
Neisseria gonorrhoeae
Meningococcaemia
Pustules and epidermal necrosis sometimes
Septic neutrophilic vasculitis, with more lymphocytes in the chronic form
Extravasated erythrocytes and thrombi
Gram-negative diplococci seldom demonstrated
Neisseria meningitidis
Ecthyma gangrenosum
Epidermal necrosis or ulceration
Dermal necrosis or infarction
Sparse inflammation with lymphocytes or neutrophils
Numerous gram-negative bacilli in dermis stain poorly with H&E
Vasculitis and thrombi common
Pseudomonas aeruginosa
Malakoplakia
Diffuse infiltrate of granular von Hansemann histiocytes containing Michaelis-Gutmann bodies (5-15 micron granules that stain positive with PAS, von Kossa and Perl’s stain)
Diffuse neutrophils, plasma cells or lymphocytes may be present
Escherichia coli
Dermatophytosis
Neutrophils sometimes in the stratum corneum, parakeratosis often
Compact orthokeratosis rather than normal basket-weave pattern
Sandwich sign (orthokeratosis or parakeratosis alternated in layers with basket-weave stratum corneum, often a clue for the presence of hyphae)
Spongiosis or intraepidermal vesicles (sometimes)
Psoriasiform epidermis (sometimes)
Folliculitis (sometimes)
Variable inflammatory response: may appear normal, or perivascular or diffuse mixed infiltrate of lymphocytes, histiocytes, neutrophils, or eosinophils
Fungal hyphae (2-4 microns in diameer) in stratum corneum or in follicles - best seen with PAS or GMS stains
Tinea versicolor
Normal-appearing skin without inflammation or with minimal perivascular lymphocytes
Short hyphae and budding yeast from 2-4 microns in stratum corneum or in follicles
Easier to see in H&E compared to dermatophytes, but are best seen with PAS or GMS stains
Tinea nigra
Skin may look normal with H&E stain at scanning magnification
Brown septate hyphae in stratum corneum can be seen with H&E stain
Candidiasis
Neutrophils, parakeratosis, and crusting common in stratum corneum
Pseudohyphae and budding yeast in the stratum corneum (3-7 microns) which can sometimes be seen with H&E, but are more easily seen with PAS or GMS stains
Perivascular lymphocytes and neutrophils in the dermis
Cryptococcosis - gelatinous pattern
Epidermis unremarkable
Budding yeast (5-20 microns) are numerous in the dermis, staining faintly with H&E or better with GMS
Prominent capsule around organisms that does not stain with H&E giving the dermis a vacuolated gelatinous appearance
Capsule contains mucin
Very little inflammatory response
Cryptococcis neoformans
Cryptococcosis - granulomatous pattern
Often ulcerated with pseudoepitheliomatous hyperplasia
Yeasts are small (2-10 microns) and less numerous: free in tissue or within histiocytes/giant cells
Dense mixed dermal granulomatous infiltrate of many neutrophils, histiocytes, giant cells and plasma cells
Cryptococcus neoformans
Coccidioidomycosis
Pseudoepitheliomatous hyperplasia in older lesions, sometimes intraepidermal neutrophilic microabscesses
Diffuse suppurative granulomatous dermal infiltrate of neutrophils, lymphocytes, histiocytes, plasma cells (and multinucleated giant cells in older lesions), and often many eosinophils.
Sometimes caseation Large thick-walled spores measuring 10–80 microns with a granular cytoplasm or containing 2–10-micron endospores.
Often visible with H&E, but best seen with PAS or GMS stains
Coccidioides immitis/posadasii
South American blastomycosis
Pseudoepitheliomatous hyperplasia, sometimes intraepidermal neutrophilic microabscesses
Diffuse mixed dermal infiltrate of neutrophils (often abscesses), lymphocytes, histiocytes, plasma cells and multinucleated giant cells
Spores 5-20 microns
Organisms up to 60 microns with multiple nods (marine pilot’s wheel)
Paracoccidioides brasiliensis
North American blastomycosis
Pseudoepitheliomatous hyperplasia, sometimes intraepidermal neutrophilic microabscesses
Diffuse mixed infiltrate of neutrophils (often abscesses), lymphocytes, histiocytes, plasma cells, and multinucleated giant cells; no caseation
Thick-walled spores 8–15 microns, sometimes with a characteristic broad-based bud, either within giant cells or free in the tissue.
Often visible with H&E, but seen best with PAS or GMS stains
Blastomyces dermatitidis
Histoplasmosis
Epidermis or mucosa often ulcerated
Diffuse mixed dermal infiltrate of neutrophils, lymphocytes, histiocytes, and a few giant cells, necrosis common
Sparse leukocytoclastic vasculitis infiltrate in some patients with AIDS instead of the diffuse infiltrate
Numerous small 2-4 micron spores surrounding by a clear space can be seen within histiocytes and giant cells with H&E stains
Seen more readily with PAS, GMS, Giemsa, Gram stains
Histoplasma capsulatum
Chromoblastomycosis
Pseudoepitheliomatous hyperplasia; sometimes intraepidermal neutrophilic microabscesses
Diffuse mixed dermal infiltrate of neutrophils (often abscesses), lymphocytes, histiocytes, plasma cells, and multinucleated giant cells; no caseation
Clusters or chains of brown spores (Medlar bodies, “copper pennies”) of 6–12 microns within histiocytes in microabscesses, as well as free within the tissue.
Spores reproduce by fission instead of budding
Phialophora, Fonsecaea, and Cladosporium
Sporotrichosis
Pseudoepitheliomatous hyperplasia; often with intraepidermal neutrophilic microabscesses or ulceration
Diffuse mixed dermal infiltrate of neutrophils (often abscesses), histiocytes, plasma cells, and multinucleated giant cells
Round, oval, or cigar-shaped spores range of 3–8 microns but are often difficult to find, even with PAS and GMS stains
Rarely, eosinophilic star-like deposits around the yeast (asteroid bodies), not to be confused with the intracytoplasmic asteroid bodies sometimes seen with sarcoidosis
Sporotrichum schenckii
Zygomycosis
Epidermis often ulcerated
Granulation tissue, thrombi, necrosis
Sparse inflammation in many cases, or neutrophilic abscesses may be present
Non-septate (coenocytic), large hyphae (diameter up to 30 microns) with right-angled branching are seen with H&E, but are best seen with PAS or GMS stains
Rhizopus, Mucor, or Absidia
Aspergillosis
Diffuse mixed dermal infiltrate of neutrophils, lymphocytes, histiocytes, or multinucleated giant cells.
Often a predominance of dermal necrosis with very little inflammation
Septate hyphae with branching at acute angles in dermis and often in blood vessels
Aspergillus immunostain available
Mycetoma (Eumycetoma: fungi, Actinomycetoma: bacteria)
Abscesses of neutrophils, mixed infiltrate, granulomatous inflammation, and/or granulation tissue, with fibrosis in older lesions
Granules (sclerotia) large colonies of organisms usually 0.5mm-3mm, large enough to see grossly
Bacteria granules (sulfur granules) whitish/yellowish <1 micron thick
Fungi granules (brown or black) with thicker hyphae at 5 microns
Actino: Nocardia, Actinomadura, Streptomyces
Eu: Pseudoallescheria boydiii, Aspergillus, Curvularia, Madurella
Rhinosporidiosis
Polypod lesions of granulation tissue with mixed inflammatory infiltrate
Characteristic numerous huge sporangia (up to 500 microns) containing endospores
Rhinosporidium seeberi
Lobomycosis
Granulomatous inflammation with multinucleated giant cells, plasma cells, and lymphocytes
Prominent fibrosis Spores are uniform in size (6-12 microns), easily seen with H&E, and form a string of pearls chain
Lacazia loboi
Pheohyphomycosis
Brown hyphae (dematiacious hyphae) found in the dermis or subcutaneous tissue
Variable mixed inflammatory reaction, suppurative granulomatous often, fibrosis often
Walled-off cystic space (pheomycotic cyst) sometimes
Foreign body may be present
Alternaria, Bipolaris, Curvularia, Exophiala, Exserohilum, and Phialophora
Hyalohyphomycosis
Necrosis often prominent
Inflammation may be sparse, or suppurative, and granulomatous
Non-pigmented hyalinised septate hyphae often visible with H&E, better seen with PAS or GMS stains
(non-pigmnted septate hyphae)
Acremonium, fusarium, penicillium
Talaromycosis
Diffuse suppurative granulomatous inflammation
Necrosis prominent with sparse inflammation in patients with poor immunity
Yeast with diameter of 3 microns in histiocytes, up to 8 microns when extracellular, dividing by binary fission without buds, appearing elongated and septate
Positive staining of yeast with PAS and GMS but not with mucicarmine
Human papillomavirus infection
Hyperkeratosis, papillomatosis, hypergranulosis
Columns of parakeratosis especially over projecting dermal papillae V
acuolated superficial keratinocytes with pyknotic raisin-like nuclei (koilocytes)
Rete ridges often slow inward at borders of lesion (arborisation, toeing inward)
Dilated capillaries in dermal papillae
Perivascular lymphocytes
Herpes simplex / varicella zoster
HSV and VZV can not be distinguished with routine H&E staining
Intraepidermal vesicle or ulceration may not be present in early lesions
Epidermal necrosis and ballooning degeneration: herpetic cytopathic changes are enlarged and pale keratinocytes, with steel-gray nuclei, margination of chromatin at the edge of the nucleus, sometimes with pink intranuclear inclusions surrounded by an artifactual cleft, acantholysis or multinucleated keratinocyte formation
Extravasated erythrocytes often
Perivascular and diffuse lymphocytes or neutrophils, sometimes with changes of leukocytoclastic vasculitis
Smallpox / vaccinia
Intraepidermal vesicles with few balloon cells (usually not multinucleated) and inclusion bodies that are primarily intracytoplasmic (Guarnieri bodies)
Mixed diffuse dermal infiltrate of lymphocytes and neutrophils
Molluscum contagiosum
Epidermal hyperplasia producing a crater filled with molluscum bodies (Henderson-Patterson bodies) that are huge, up to 35 microns, eosinophilic to basophilic intracytoplasmic inclusions that push the nucleus and numerous keratohyaline granules aside Intact lesions show little or no inflammation, while ruptured lesions exhibit dense mixed inflammatory response consisting of mononuclear cells, neutrophils, and multinucleated giant cells
Rarely, CD30+ atypical reactive lymphocytes resemble lymphoma
Orf and Milker’s nodule (farmyard pox)
Vacuolated superficial epidermis with inclusion bodies that are predominantly intracytoplasmic, occasionally intranuclear
Epidermal necrosis, often with extremely delicate finger-like projections into the dermis
Dense, diffuse, mixed inflammatory infiltrate in the dermis
Dermal oedema, extravasated erythrocytes, dilated blood vessels
Coxsackie virus infection
Intraepidermal multiloculated vesicles or pustules
Epidermal necrosis, or ballooning degeneration without inclusion bodies or multinucleated keratinocytes
Papillary dermal oedema, sometimes resulting in subepidermal blisters
Perivascular lymphocytes or neutrophils
Viral exanthem
Epidermis normal or with focal parakeratosis or focal spongiosis
Mild ballooning degeneration or multinucleated keratinocytes rarely (not as prominent as seen with herpes viruses) or focal keratinocyte necrosis
Perivascular or interface lymphocytes
CMV
Epidermis normal, verrucous or ulcerated
Vascular dilation with large cytomegalic endothelial cells Intranuclear and intracytoplasmic inclusion bodies (owl eye appearance)
Variable lymphocytes or neutrophils
Positive CMV immunostain
Viral particles indistinguishable from other herpes viruses by electron microscopy
Kawasaki’s disease
Non-specific perivascular lymphocytes (not neutrophils) in biopsies from the rash
Gianotti-crosti syndrome
Focal parakeratosis, sometimes crusting
Focal spongiosis, acanthosis, dyskeratosis
Papillary dermal oedema often
Perivascular lymphocytes, rare eosinophils
Extravasated red blood cells sometimes
Rickettsial diseases
Epidermal necrosis, or spongiosis at initial bite site
Dermal oedema, or subepidermal blister in rickettsialpox, which may appear to be intraepidermal after re-epithelialisation
Vasculitis with predominance of lymphocytes and histiocytes, although some cases are neutrophilic
Extravasated erythrocytes and thrombi often
Organisms are difficult to demonstrate by special stains such as Giemsa, but direct immunofluorescence and immunoenzyme antibodies demonstrating the organisms in frozen sections are available
Lymphogranuloma venereum
Epidermis normal or ulcerated
Diffuse mixed infiltrate of neutrophils, lymphocytes, histiocytes, plasma cells and sometimes multinucleated giant cells
Stellate abscesses often in lymph nodes, later becoming granulomatous
Organisms rarely demonstrated with Giemsa stain in histiocytes
Chlamydia trachomatis (L1-L3)
Leishmaniasis
Epidermis normal, atrophic, hyperplastic or ulcerated
Diffuse mixed granulomatous dermal infiltrate of lymphocytes, histiocytes, plasma cells, neutrophils, and multinucleated giant cells, occasional caseation necrosis
Fibrosis in older lesions
Amastigote organisms are usually present within histiocytes 2-3 microns, 1-micron round nucleus (H&E or Giemsa or Tzanck smear)
Protothecosis
Epidermis ulcerated or hyperplastic
Mixed diffuse infiltrate of neutrophils, lymphocytes, histiocytes and multinucleated giant cells
Dermal necrosis common
Organisms usually visible with H&E but highlighted with PAS, GMS, acid mucopolysaccharide stains 2-11 microns in size
Can look like soccer balls
Prototheca spp
Cysticercosis
Larva (cysticercus, 6-18mm long), secretory tegument surrounded by a unilocular cystic cavity and fibrosis in subcutaneous tissue, usually in subcutaneous or deeper soft tissue, often pale and necrotic
Scolex (mouth), is important to find on deeper levels, with sucking grooves known as bothria
Calcareous bodies (oval calcified focal concretions)
Very little inflammation until larva dies: mixed inflammatory infiltrate with sometimes calcification
Taenia solium
Dirofilariasis
Tightly-coiled solitary worm with a thick cuticle, considerable muscle, and diameter of 125-250 microns, usually in subcutaneous tissues
Mixed inflammatory infiltrate with lymphocytes, histiocytes, plasma cells, eosinophils, multinucleated giant cells
Onchocerciasis
Onchocercoma: adult worms (100-500microns in diameter) live in orgies within nodules in the subcutaneous tissue, surrounded by dense fibrosis, or multinucleated giant cells.
Female worms have paired uteri
Dermatitis: microfilariae (5-9 microns) are found within adult female worms or migrating freely in the dermis
Cutaneous larval migrans
Scale, crust, spongiosis, or intraepidermal vesicle containing eosinophils
Dermal oedema Perivascular lymphocytes, histiocytes, and many eosinophils
Larva (about 0.5mm thick and up to 10mm long) difficult to find, usually in deeper epidermis
Arthropod bites and stings
Epidermis may have scale crust, epidermal necrosis, or epidermal hyperplasia
Spongiosis or intraepidermal vesicle (often)
Dermal oedema, sometimes subepidermal vesicle Perivascular (usually superficial and deep) neutrophils, lymphocytes (sometimes atypical or CD30+), or eosinophils, older lesions show diffuse or nodular inflammation similar to lymphocytoma cutis
Endothelial swelling (often)
Demodicosis
Folliculorum within hair follicles (100-400microns)
Brevis within sebaceous glands
Variable inflammatory reaction Lymphocytes in the pilosebaceous unit, sometimes suppurative or granulomatous inflammation
Scabies
Eggs or mites (200-400 microns) or scybala (brown faces) are present in the sub corneal zone
Sometimes spongiosis or epidermal hyperplasia
Perivascular or moderately diffuse dermal lymphocytes and eosinophils
Myiasis
Maggots found in dermis or subcutaneous tissue with characteristics depending upon the species, many have thick corrugated skeletal wall
Dermatobia hominis is a more commonly encountered maggot in South America
Diffuse mixed infiltrate of lymphocytes, histiocytes, and eosinophils
Tungiasis
Hyperkeratosis, acanthosis, crusting
Female flea beneath stratum corneum may reach 5mm in diameter when becomes swollen with eggs
Skeletal muscle and red hollow tubules present
Mixed inflammatory infiltrate, sometimes abscess formation
Pneumocystosis
Foamy stroma with H&E stain
Round, no-budding 5-10 micron cysts (teacup in saucer appearance) in the dermis or subcutaneous tissue are best stained with GMS
Amebiasis
Ulceration or pseudoepitheliomatous hyperplasia
Granulation tissue, dermal oedema, necrosis, fibrosis
Mixed diffuse inflammation, may be granulomatous
Trophozoites resembling epithelioid histiocytes, 15-40 microns, with a bubbly or granular cytoplasm and single nuclear that has marginated chromatin may be seen with H&E, but are more easily seen with PAS
Erythrophagocytosis by trophozoites (sometimes)
Some species can be cultured or PCR/IF
Trypanosomiasis
Ulceration or epithelial hyperplasia
Mixed inflammation: histiocytes, plasma cells, lymphocytes
Trypanosomes have a nucleus and kinetoplast that is Giemsa stain positive
Toxoplasmosis
Pseudoepitheliomatous hyperplasia or epidermal necrosis (sometimes)
Perivascular or interface lymphocytes and macrophages
Dermal necrosis and extravasated erythrocytes (sometimes)
Trophozoites (2-8 microns) or cysts (8-30 microns), containing numerous smaller bradyzoites are found in macrophages or free in the dermis in half of the cases, some forms are PAS positive
Immunostains, serology and PCR detection is available
Schistosomiasis
Granulomas and neutrophils around eggs (up to 120 microns long, some are PAS or AFB stain positive)
Egg spine positions determine species / geographic origin too
Adult worms rarely seen in blood vessels
Erythema nodosum
Septal panniculitis of lymphocytes, histiocytes, neutrophils and/or eosinophils
Multinucleated giant cells in older lesions without caseation
Septal fibrosis in older lesions
Mild fat necrosis sometimes with foamy histiocytes
Weber-Christian disease / Anti-phospholipid syndrome
Lobular panniculitis with neutrophils, lymphocytes (sometimes mixed with a septal pattern)
Fat necrosis with foamy macrophages
Cystic spaces may occur in dissolved fat lobules
Necrosis and inflammation may spill over in the dermis, resulting in necrosis draining through ulcers
Fibrosis in late lesions
Cold panniculitis
Lobular panniculitis of neutrophils, lymphocytes, and histiocytes
Cystic spaces in subcutaneous fat due to ruptured fat cells
Sclerema neonatorum
Needle-shaped clefts within fat cells and foamy histiocytes
Mild fat necrosis surrounded by sparse or absent granulomatous infiltrate of lymphocytes, histiocytes and multinucleated giant cells
Prominent sclerosis or fibrosis
Subcutaneous fat necrosis of the newborn
Needle-shaped clefts within fat cells, and foamy histiocytes
Fat necrosis and granulomatous infiltrate of lymphocytes, histiocytes and multinucleated giant cells
Calcification common
Erythema induratum
Ulceration sometimes
Lobular granulomatous panniculitis with mixed infiltrate of lymphocytes, histiocytes, plasma cells and multinucleated giant cells
Caseation necrosis sometimes
Vasculitis in the fat often involving arteries or small veins
Fibrosis in older lesions
Superficial thrombophlebitis
Mixed infiltrate of neutrophils, lymphocytes, histiocytes, or multinucleated giant cells within and surrounding a vein in the deep dermis or subcutaneous fat
Thrombosis frequent
Pancreatic panniculitis
Mixed lobular panniculitis with lymphocytes, foamy histiocytes, and multinucleated giant cells
Fat necrosis with “ghost-like” fat cells and basophilic deposits of calcium salts of fatty acids
Lipodermatosclerosis
Epidermal or dermal changes similar to stasis dermatitis
Fat necrosis, sclerosis, foamy macrophages, lymphocytes, in a diffuse or lobular pattern
Lipodystrophy
Early lesions may show the inflammatory patter in the fat, fat necrosis with foam lipophages, plasma cells and lymphocytes with relatively normal lipocytes and blood vessels
Other early lesions may show the involution pattern in the fat: small lipocytes, hyalinisation, myxoid changes, increased number of small blood vessels
Late lesions have a profound decrease or absence of fat
Acrodermatitis enteropathica
Scale crust often, with confluent parakeratosis, fibrin and neutrophils in the stratum corneum.
Sometimes bacteria and candida
Hypogranulosis
Psoriasiform hyperplasia, spongiosis, sometimes intraepidermal vesicles
Pale, or dyskeratotic epidermis
Perivascular lymphocytes
Vitiligo
Decreased or absent melanin and melanocytes in basal layer in well-developed lesions (often difficult to appreciate with H&E staining, and require special stains)
Hyperkeratosis and acanthosis can sometimes develop to compensate for loss of pigment
Perivascular lymphocytes only in early lesions
Graft vs host disease
Epidermal atrophy (sometimes)
Mild spongiosis (sometimes)
Grade 1: liquefaction degeneration (vacuolar alteration) of the basal layer
Grade 2: dyskeratotic or necrotic keratinocytes, sometimes with adjacent lymphocytes (satellite cell necrosis), sparse perivascular or interface dermatitis, melanin incontinence (sometimes)
Grade 3: sub-epidermal microvesicle
Grade 4: frank subepidermal blister, complete epidermal necrosis in severe cases
Aplasia cutis congenita
Epidermal atrophy with superficial or deep ulcer
Dermal atrophy, fibrosis with absent adnexa
Lymphocytes and neutrophils associated with ulcer
Polymorphous light eruption
Variable histology depending upon the type of lesion
Spongiosis or intraepidermal vesicles sometimes
Necrotic keratinocytes sometimes
Usually no liquefaction degeneration of the basal layer
Superficial dermal oedema or subepidermal vesicle sometimes
Superficial and deep perivascular or nodular lymphocytes, usually spares follicles
Negative DIF for immunoglobulin and complement deposition
Lupus erythematosus
Hyperkeratosis (sometimes)
Follicular plugging
Epidermal atrophy or hyperplasia
Colloid bodies sometimes in basilar epidermis or papillary dermis
Liquefaction degeneration of the basal layer
Melanin incontinence
Thickened basement membrane
Increased mucin in dermis
Perivascular and periadnexal, sometimes lichenoid, lymphocytes with occasional plasma cells, but almost always no eosinophils
Immunofluorescence reveals granular deposits of IgM, IgG and complement at DEJ - positive staining both lesional and normal skin indicated SLE
Dermatomyositis
Usually more subtle than lupus erythematosus
Epidermis atrophic or normal
Liquefaction degeneration of basal layer
Thickened basement membrane (sometimes)
Dermal oedema
Dermal mucin
Sparse perivascular or interface lymphocytes
Sometimes dermal or subcutaneous calcifications
DIF usually negative
Relapsing polychondritis
Perichondrial inflammation (neutrophils, lymphocytes, or plasma cells)
Degeneration of cartilage with loss of chondroitin sulphate (decreased basophilia) and vacuolisation of chrondrocytes
Perichondrial fibrosis in older lesions
Chondrodermatitis nodularis
Hyperplasia of epidermis, often with focal ulceration
Granulation tissue, fibrosis, solar elastosis and mixed inflammatory infiltrate (lymphocytes, neutrophils, plasma cells) between ulcer and underlying cartilage
Degeneration of cartilage, often with blending with fibrosis, sometimes with transepidermal elimination
Epidermal naevus
Hyperkeratosis, papillomatosis, acanthosis, sometimes hypergranulosis
Epidermolytic hyperkeratosis (rarely)
Acantholytic dyskeratosis (rarely)
Perivascular lymphocytes (often)
Seborrhoeic keratosis
Epidermal proliferation (variable combinations of hyperkeratosis, papillomatosis, acanthosis)
Keratinocytes often appear basaloid Horn pseudocysts (often)
Abundant melanin in basal layer or throughout epidermis
Sharp demarcation (string sign) of base of epidermal proliferation
Acrokeratosis verruciformis
Orthokeratosis, hypergranulosis, acanthosis
Papillomatosis, often resembling church spires
Porokeratosis
Cornoid lamella: column of parakerotosis under which there is hypogranulosis and keratinocytes with dyskeratosis or pale staining
Epidermis in central part of lesion may be normal, hyperplastic, or atrophic
Perivascular or lichenoid lymphocytes, sometimes localised beneath cornoid lamella
Acanthosis nigricans
Hyperkeratosis, papillomatosis
Acanthosis minimal/or absent (misnomer)
Basal layer hyperpigmentation (often)
Clear cell acanthoma
Scale-crust on surface of epidermis (often)
Neutrophils in epidermis, often with microabscesses in stratum corneum
Psoriasiform proliferation of pale (clear) keratinocytes, with sharp demarcation from normal epidermis
Perivascular lymphocytes
Dilated blood vessels in oedematous pale dermal papillae
Warty dyskeratoma
Comedo-like invagination of epidermis filled with hyperkeratosis, parakeratosis, acantholytic, dyskeratotic keratinocytes (corps ronds/grains)
Dermal papillae lined by basal cells may project up into the invagination resembling villi
Actinic keratosis
Hyperkeratosis (often), ulceration (sometimes)
Parakeratosis, especially overlying atypical keratinocytes often sparing epidermis over adnexa (alternating pink and blue hue in corneum: flag sign)
Atypical keratinocytes, (sometimes subtle), with loss of orderly keratinocyte maturation, hyperchromatism, pleomorphism, increased mitoses, dyskeratosis, sparing epidermis above adnexa, too many buds into the papillary dermis
Perivascular or lichenoid lymphocytes, sometimes plasma cells
Solar elastosis in the dermis
Arsenical keratosis
Hyperkeratosis, acanthosis
Cytologic atypic of keratinocytes often, may represent SCCIS
Variable perivascular lymphocytes in dermis
Bowen disease
Parakeratosis, hyperkeratosis, acanthosis
Atypical keratinocytes with hyperchromatism, pleomorphism, increased atypical mitoses, dyskeratosis, loss of orderly maturation through the epidermis.
Full thickness atypic
Clear cells or pagetoid cells can be prominent in some cases
Perivascular or lichenoid infiltrate of lymphocytes or plasma cells
Squamous cell carcinoma
Invasion of dermis by atypical keratinocytes (hyper chromatic, pleomorphic cells, often epithelioid, with atypical mitoses)
Squamous eddies or keratin pearls (sometimes)
Variable perivascular, lichenoid or diffuse lymphocytes or plasma cells
Perineural invasion in some aggressive forms (more common than in BCC)
Keratoacanthoma
Keratin-filled crater
Pale, eosinophilic glassy, well-differentiated epithelial proliferation, often with lips extending over both sides of crater, often with squamous eddies or keratin pearls
Sometimes microabscesses of neutrophils within the epithelium
Cytologic atypic of keratinocytes no more than mild
Elastic fibres sometimes found within epithelium of base of lesion
Perivascular or lichenoid infiltrate of lymphocytes, sometimes with eosinophils or plasma cells
Paget disease
Pale staining Paget’s cells often with atypical nuclei scattered through the epidermis
Groups of them may compress and flatten basal cells, appearing like the eyeliner sign found sometimes in Bowen disease
May appear multifocal with skip areas
Usually no dyskeratosis, unlike Bowen disease
Paget cells usually positive for CEA, EMA, androgen receptor, keratin 8 (low molecular weight), or cam5.2, or CK7, PAS with or without diastase, alcian blue, mucicarmine
CK20 commonly associated with perianal cases
Gross cystic disease fluid protein often positive (less common with internal malignancy)
Underlying adenocarcinoma sometimes seen within dermis
Basal cell carcinoma
Ulceration of epidermis sometimes
Basaloid tumour cells budding from epidermis or follicles or within the dermis with variable atypia
Retraction artifact, stroma separates from tumour lobules, often but often absent on frozen sections
Peripheral palisading of nuclei (often)
Mucin in the stroma or with basaloid aggregates (often)
Solar elastosis in the dermis
Perineural invasion in some aggressive forms
Variable infiltrate of lymphocytes, plasma cells, rarely lymphoid follicles around the tumour
Onychomatricoma
Fibroepithelial digitations with bland epithelial strands or solid aggregates with invaginated fibrous stroma, sometimes giving the appearance of Swiss cheese holes in the epithelial aggregates
Follicular infundibulum cyst
Cyst contains lamellated keratin
Cyst lined by squamous epithelium, sometimes flattened, with a granular layer
Pilar cyst
Cyst contains amorphous, dense and compact, homogenized keratin
Cyst lined by squamous epithelium
The keratinocytes are often pale, and there is no granular layer
Calcification common within the cyst
Dermoid cyst
Cyst contains lamellated keratin and often hair shafts
Cyst lined by by squamous epithelium with a granular layer
Multiple hair follicles open into the cyst, sometimes with sebaceous glands or sweat glands
Vellus hair cyst
Cyst is small and contains lamellated keratin and vellus hair shafts
Cyst lined by squamous epithelium with a granular layer
Hair follicles sometimes attached to cyst
Steatocystoma
Cyst may contain sparse keratin or hair shafts, but frequently appears empty because the oily sebaceous fluid dissolves during processing
Cyst wall consists of ruggated squamous epithelium with a wrinkled crenulated (wavy or serrate outline) eosinophilic refractile cuticle of keratin instead of a granular layer, often resembling shark’s teeth.
Sebaceous glands within or adjacent to the cyst wall, opening into the cyst
Cervical thymic cyst
Cyst is often multilocular and appears empty because fluid washes out during processing
Cyst wall varies from cuboidal, ciliated, and non-ciliated columnar to squamous epithelium
Thymic tissue (aggreagates of immature and mature lymphocytes) with Hassall’s corpuscles (concentrically hyalinised collection of degenerating cells of 20-50 microns, sometimes calcified)
Cholesterol clefts, granulomatous inflammation common
Cutaneous ciliated cyst
Cyst usually appears empty because fluid runs out after biopsy
Cyst lining consists of cuboidal or columnar ciliated epithelium, without goblet (mucin-secreting) cells
Thyroglossal duct cyst
Cyst contains keratin or mucin
Cyst lining varies from pseudostratified columnar (with or without goblet cells or cilia) to squamous epithelium. No smooth muscle, mucous glands, or cartilage adjacent to lining
Thyroid follicles or lymphoid follicles may be present
Branchial cleft cyst
Cyst contains laminated keratin
Sinus tract or cyst lined by squamous epithelium with a granular layer, or by columnar epithelium with or without cilia or goblet (mucus-secreting) cells
Cysts often surrounded by lymphoid follicles
Bronchogenic cyst
Cyst contains keratin or mucin
Cyst lining varies from pseudostratified columnar (with or without goblet cells or cilia) to squamous epithelium
Lining may be surrounded by mucous glands, smooth muscle, lymphoid follicles, or cartilage
Hidrocystoma
Cyst appears empty because fluid leaks out
Cyst lined by thin cuboidal or columnar epithelium (often two layers of cells)
Median raphe cyst of the penis
Cyst appears empty because fluid leaks out after biopsy
Cyst lined by pseudostratified columnar epithelium
Auricular pseudocyst
Intracartilaginous cystic space with degenerated cartilage and amorphous eosinophilic material
Fibrosis, granulation tissue or granulomatous inflammation may be present
Freckle
Increased melanin in basal layer
Normal or decreased number of more active melanocytes
No elongation of rete ridges or nesting of melanocytes
Cafe-au-lait spot
Increased melanin in the basal layer
Normal number of melanocytes (although may slight increase in NF-1 CALMs)
No elongation of rete ridges or nesting of melanocytes
Macromelanosomes
Lentigo simplex
Hyperpigmented, often elongated rete ridges, usually with increased melanocyes
No nests of melanocytes
No solar elastosis
Solar lentigo
Hyperpigmented basal layer, often with elongated, clubbed rete ridges (“dirty feet”), usually with increased melanocytes
No nests of melanocytes
Solar elastosis
Melanocytic naevus
Epidermal changes vary greatly: atrophy, hyperplasia, papillomatosis, or horn cysts may be present
Nests (theques) or cords of melanocytes (“nevus cells”) at the dermal–epidermal junction or in the dermis. Nevus cells vary greatly in size and shape, and melanin may or may not be present (melanin most likely to be present in junctional nests or upper dermal nests).
Type A nevus cells are usually present in the junctional zone or superficial dermis, and appear epithelioid (more cytoplasm, larger, pale nucleus).
Type B nevus cells are usually present in the mid-dermis and resemble lymphocytes (less cytoplasm, small dark nucleus).
Type C nevus cells are usually present in the deeper dermis; they are more spindled and have considerable pink cytoplasm, and may form neuroid structures.
A fourth type of nevus cell is the nevus multinucleated giant cell. These are usually more prevalent in the superficial dermis and have clumped nuclei, but sometime they exhibit a rosette of nuclei
Usually no inflammation, unless the lesion is irritated
Spitz naevus
Symmetrical sharply demarcated lesion
Epidermal hyperplasia with rete reidges often clutching melanocytic nests
Melanocytic nests (junctional, dermal, or compound), spindle-shaped or epithelioid, or both
Clefts, often around melanocytic nests, sometimes pagetoid
Bizarre multinucleated or atypical melanocytes often in superficial portion of lesion, sometimes with mitoses limited to superificial portion, often with angulated or vertically orientated shape
Maturation
Melanin absent, sparse or prevalent
Hyaline (Kamino) bodies sometimes at DEJ
Vascular dilation
Lymphocytic infiltrate more likely patchy than lichenoid
HRAS mutations 10-30%, ALK1 10%, NTRK 16%, BRAF 5%
Dysplastic naevus
Elongated, clubbed rete ridges often similar to a lentigo
Poorly circumscribed melanocytic nests at the dermal–epidermal jnction, often bridging between rete ridges. Single melanocytes predominant over nests (so-called lentiginous hyperplasia)
Junctional melanocytes often extend beyond the dermal melanocytes at the periphery of the lesion (shoulder phenomenon) if it has a dermal component
Cytologic atypia of melanocytes (absent in most cases per some authors, including this author, while others say it is the most important feature!). Nuclear size has been used as part of the grading: mild = melanocytic nuclear size less than 1.5 × the size of basal keratinocytes, moderate = 1.5–2 ×, and severe 2 ×
Maturation of melanocytes in the dermis if dermal nests are present (cells are smaller and less atypical in deepest portion)
Fibroplasia in the papillary dermis around the junctional melanocytes, as if the body is walling off these melanocytes with collagen. Some think this is just compression of collagen by elongated rete ridges
Mild to moderate perivascular lymphocytes in the dermis. An ordinary nevus should not have lymphocytes within it unless it is an irritated, halo, or Spitz nevus
Blue naevus
Epidermis normal
Spindle-shaped dendritic melanocytes in the dermis associateed withi abundant fine granules of melanin
Melanophages, macrophages that have phagocytized clumps of melanin
Sclerosis of collagen common
GNAQ mutation in about 50-80%, GNA11 mutation in about 7%
Naevus of Ota / Naevus of Ito
Epidermis is normal
Spindle-shaped dendritic melanocytes in the dermis associated with abundant fine granules of melanin
Melanophages usually not present
Mongolian spot
Epidermis normal
Spindle-shaped dendritic melanocytes in the deep dermis associated with abundant fine granules of melanin
Melanophages usually not present
Melanoma
Epidermis is normal, atorphic, hyperplastic or ulcerated (worse prognosis)
Asymmetrical proliferation of melanocytes, often with poorly demarcateed border (except in nodular melanoma)
Atypical melanocytes, small, spindled or epithelioid, often with finely dusted with melanin, arise at the dermal-epidermal junction and invade the dermis
Mitoses are often not present
Poor maturation
Pagetoid melanocytes often
Lymphatic/vascular invasion may be present
Lichenoid lymphocytes in the dermis (perivascular less often) or sparse
Precursor lesion (1/3 of cases)
Regression - vascular fibrous tissue in the papillary dermis, sometimes with melanophages
Sebaceous hyperplasia
Enlarged, otherwise normal sebaceous gland, often with a large central orifice
Solar elastosis frequent
Naevus sebaceous
Epidermal hyperplasia and papillomatosis
Many normal or enlarged sebaceous glands, usually unassociated with mature hair shafts. Early in childhood, the entire pilosebaceous unit is poorly developed and appears as small buds
Many apocrine glands
Basaloid hyperplasia, true basal cell carcinoma (BCC, less than 5% incidence, some authors call them trichoblastoma instead) syringocystadenoma papilliferum, trichilemmoma, or other adnexal tumors commonly develop within a nevus sebaceus after puberty
Sebaceous adenoma
Distinctly circumscribed lobular tumor of mature sebaceous cells (sebocytes, which may have a crenulated outline or surface indented by the sebaceous material) and basaloid (germinative) cells, with about 50% or more of the cells being mature sebaceous cells
Minimal cytologic atypia, although mitoses may be prevalent in some lesions
Basal cell carcinoma with sebaceous differentiation
Features of BCC (18.14) with less than 30% mature sebocytes (often only focal areas).
Sebaceous carcinoma
Pagetoid cells sometimes in the epidermis or conjunctiva
Disordered invasion of dermis by poorly defined lobules of basaloid or squamoid cells and poorly developed sebaceous cells
Moderate to severe atypia
Oil-red-O or Sudan black stain for lipid: must be done with frozen section
Positive staining fo EMA, is more weekly positive or negative in both BCC and SCC
Androgen receptor often positive (unlike BCC/SCC)
Adipophilin positive in a membranous pattern (as opposed to granular patterin in clear cell SCC or BCC)
Trichofolliculoma
Large open or closed comedo-like lesions (sometimes resembling a cyst if there is no orifice) into which numerous small hair follicles with trichohyaline granules and vellus hairs open
Fibrotic stroma
Trichoepithelioma
Circumscribed basaloid tumour islands, often in a reticulated pattern or cribriform pattern, sometimes resembling poorly developed hair follicles
Horn cysts common
Peripheral palisading of nuclei, but no artifactual retraction between tumour and stroma
Loose stroma with many fibroblasts surround basaloid islands
Papillary mesenchymal bodies (clusters of fibroblasts adjacent to epithelial buds as in the germinative portion of the normal hair papilla)
Brooke-Spiegler association
Pilomatrixoma
Circumscribed nodule resembling a cyst in the dermis, sometimes with a squamous epithelial lining of the periphery
Basaloid cells in younger lesions, especially around periphery of nodule. Mitoses common even in benign lesions
Shadow (ghost) cells, which have a pale, empty space where the nucleus used to be, with abundant pink cytoplasm. Transitional cells may be present, not to be confused with transitional epithelium, with pyknotic nuclei in the process of becoming shadow cells
Shards of keratinous debris, shadow cells, calcification, or ossification may be predominant in older lesions (basaloid cells gradually decrease in number)
Foreign body multinucleated giant cells and granulomatous inflammation (1.51) often present as a reaction to abundant keratin
Gardner syndrome and myotonic dystrophy
Proliferating pilar cyst
Arises in a pilar cyst
Proliferated wall with squamous eddies and paerls
Abrupt trichilemmal keratinisation without a granular layer
Clear cells sometimes present
Can be malignant
Trichilemmoma
Hyperkeratosis with downward lobular growth of epidermis
Keratinocytes are clear cells because of glycogen within the cells (PAS positive, diastase labile)
Thin rim of basal cells palisade at edge of lobule of clear cells
Thickened basement membrane sometimes (PAS positive, diastase resistant)
CD34 and pankeratin is positive in the epithelial cells, but not commonly done
Cowden, Bannayan-Riley, Proteus (PTEN mutations)
Fibrofolliculoma and trichodiscoma
Hair follicle with thin extensions of epithelium into surrounding mucinous stroma (fibrofolliculoma)
Loose fibrosis with thin collagen bundles and blood vessels localised to a subepidermal area adjacent to a hair follicle without follicular extension in older lesions (trichodiscoma)
Birt-Hogg-Dube
Trichoblastoma
Circumscribed large basaloid neoplasm usually greater than 1 cm
Location deep dermis or subcutaneous tissue
No solar elastosis, no connection to surface epithelium
No significant numbers of mitoses or cytologic atypia
Eccrine naevus / apocrine naevus
Basaloid hyperplasia of the epidermis sometimes
Increased size or number of apocrine or eccrine glands
Hidradenoma papilliferum
Circumscribed tumor in the dermis with many maze-like glandular spaces, apocrine differentiation, and papillary folds
Usually no connection of the tumor to the epidermis
Usually minimal inflammation around the tumor
Syringocystadenoma papilliferum
Papillomatous epidermis connecting to underlying tumor
Cystic space within tumor opens to surface of skin. Tumor lined by squamous epithelium in the upper portion; lower portion lined by sweat glandular epithelium
Apocrine decapitation secretion usually present (sometimes is eccrine)
Papillary projections into cystic space
Plasma cell infiltrate around tumor
Nevus sebaceus is often present as a precursor lesion
Cylindroma
Tumour of basaloid cells in the dermis arranged in islands that often fit together like a jigsaw puzzle. One type is larger and has paler nucleus than the other
Hyalinised cylinders (thickened basement membrane) around each tumour island
Hyalinised droplets often within tumour
Sweat duct lumina often present within tumour islands
Brooke–Spiegler syndrome
Papillary adenoma / nipple adenoma
Circumscribed tumor, many glandular spaces with apocrine decapitation secretion and papillary projections into the lumina, sometimes filling the lumina
Tumor often connects to surface of epidermis
Infiltrate of lymphocytes or plasma cells around the tumor sometimes
Tubular aprocrine adenoma
Epidermis sometimes hyperplastic
Circumscribed tumor in dermis or subcutaneous tissue consisting of many glandular spaces
Apocrine decapitation secretion usually present
Papillary projections without stroma extend into the lumina of the tubules
No connection to the surface epithelium
Syringoma
Proliferation of eccrine ducted structures in the dermis. When sectioned at an angle, they appear to resemble tadpoles or paisleys
No aggressive infiltration of the deeper dermis
Horn cysts may be present, and milia may coexist
Stroma is often fibrotic or sclerotic
Papillary eccrine adenoma
Circumscribed dermal tumor consisting of many glandular spaces with eccrine (sometimes apocrine) differentiation
Papillary projections into the lumina only in some portions of the neoplasm
Focal or no connection to the surface epithelium
Fibrous stroma
Positive staining for CEA and S-100
Nodular hidradenoma
Nodular tumor in the dermis or subcutaneous tissue made up of mainly one cell type of basaloid cells, sometimes with focal connection to epidermis
Sweat duct lumina usually present within the tumor, varying from small ducts to large cystic spaces
Usually eccrine differentiation, rarely apocrine decapitation secretion is present
Hyalinized collagen in the stroma sometimes
Keratinous cysts sometimes
Eccrine poroma
Tumour of cuboidal or basaloid “poroid” cells within the lower portion of an acanthotic epidermis extending into the dermis
Often sharp demarcation or moat between normal epidermis and tumour
Tumour cells may be clear due to glycogen accumulation
Small sweat ducts usually present within tumour
Eccrine spiradenoma
Sharply demarcated nodules of basaloid cells in dermis or subcutaneous tissue (“blue balls”)
Almost never any connection to the epidermis
Basaloid cells are often said to be of two types, which might not be so apparent: one is more pale with more cytoplasm than the darker cells
Basaloid cells tend to be arranged in rosettes, sometimes called trabeculae
Sparse small sweat ductal lumina usually present
Lymphocytes with Langerhans cells usually scattered in the stroma and in the epithelial aggregates
Stroma often vascular
Chondroid syringoma (mixed tumour of the skin)
Epithelial islands small to medium sweat ductal structures, eccrine or apocrine
Prominent mucinous stroma (positive with acid mucopolysaccharide stains) eventually becoming chondroid
Hyalinised areas in the stroma (sometimes)
Sweat gland carcinoma
Tumor infiltrating the dermis and consisting of ductal or glandular structures
Atypia (hyperchromatism, pleomorphism, increased numbers of mitoses) or necrosis often present
Mycoses fungoides
Epidermis may be atrophic, hyperplastic or ulcerated
Lichenoid or diffuse, less commonly just perivascular: atypical lymphocytes, sometimes with cerebriform nuclei, with eosinophils and plasma cells
Epidermotropism of the atypical lymphocytes: patrier microabscesses (less prominent in older nodules), bare underbelly sign (lymphocytes preferentially on the epidermal side of blood vessels, heading towards the epidermis)
Spongiosis usually not seen in most cases, unlike eczema. MF has too much epidermotropism for too little spongiosis (“too much for too little”)
Follicular mucinosis sometimes present
Most lymphocytes exhibit positive staining with T-cell markers (CD2, CD3, CD5), most often with increased T-helper cells (CD4) and fewer suppressor-cytotoxic T cells (CD8), the normal 2:1 ratio of CD4:CD8 is usually more than 3 : 1. Loss of pan-T-cell markers such as CD7, and less commonly CD43 or CD5, has been stressed as helpful, but this may not be as specific as advertised
Identification of CD25 (IL-2 receptor) positive cells is useful prior to therapy with denileukin diftitox (Ontak). Positive staining for CD52 is useful for possible alemtuzumab (anti-CD52, Campath) treatment. Positive staining for cytotoxic proteins (granzyme, perforin, TIA-1) indicates more aggressive subtype (some would not classify this as true mycosis fungoides)
Clonal T-cell receptor (TCR) gene rearrangements may be present in 60% of patients with patch stage MF, 65% of more advanced MF, and 20% of benign inflammatory conditions. The gene rearrangement is usually alpha–beta, but sometimes gamma–delta
Papillary dermal collagen often said to be wiry, resembling fettuccine, but this is overrated as a diagnostic help
Sezary syndrome
By definition, more than 1000 Sezary cells per cubic millimeter in the peripheral blood (large cerebriform atypical CD4 + lymphocytes greater than 14 microns). The CD4 +:CD8 + ratio is often more than 10 : 1 with flow cytometry with most cells are CD7 −. The Sezary cells are negative for CD4. CD26 loss with flow cytometry has been found in 50% of cases, but this is less important than loss of T-cell markers CD2 and CD3, since loss of CD26 is found in 33% of cases of MF, and 15% of cases of benign dermatitis.
Otherwise routine histology and immunopathology similar to MF (24.1). In some cases the skin biopsy is non-specific and the diagnosis is made from the blood.
Clonal T-cell gene rearrangments in skin or blood as in MF.
Adult T cell leukaemia/lymphoma
Histology and TCR often similar to MF
CD3+, CD4+ CD25 positive (unlike MF)
Gene rearrangements often present
Subcutaneous T cell lymphoma
Lobular panniculitis (often lace-like pattern of lymphocytes rimming adipocytes), without significant dermal or epidermal involvement The malignant small lymphocytes are usually CD3 +, CD8 +, granzyme +, TIA-1 +, perforin + (cytotoxic phenotype). Sometimes the lymphocytes may be larger with more cytologic atypia CD68 + macrophages often exhibit cytophagocytosis of erythrocytes or nuclear debris (“bean bag cells”) Sometimes an alpha–beta (α–β) T-cell receptor gene rearrangement is present (BF-1 positive)
CD30 + lymphoproliferative disorders
Epidermal necrosis often, or ulceration
Nodular infiltrate of ordinary lymphocytes, very atypical CD-30 positive activated T lymphocytes iwth epidermotropism into the epidermis
Neutrophils and eosinophils sometimes present
Extravasated erythrocytes, often with red blood cells in the epidermis
Multiple subtypes
10% risk of progression to NHL/MF
Extranodal NK/T-cell lymphoma (nasal type)
Epidermis often ulcerated, sometimes pseudocarcinomatous hyperplasia
Diffuse or perivascular polymorphous infiltrate of atypical lymphocytes, histiocytes, plasma cells, and eosinophils
Epidermotropism sometimes, invasion of adnexa and nerves common
Infiltration of blood vessel walls by lymphocytes, sometimes with changes suggesting vasculitis (necrosis of vessel walls, with thrombi, 1.145)
CD2 +, CD56 +, TIA-1 +, but with frequent loss of T-cell markers CD3, CD4, CD5, or CD7 (therefore formerly called null cells). Epstein–Barr positive (by in situ hybridization, for example)
Usually negative for gene rearrangements
Cutaneous aggressive epidermotropic CD8 + cytotoxic T-cell lymphoma
Nodular or diffuse atypical lymphocytes with prominent epidermotropism
Less involvement of the fat than the other two conditions in this section
CD3 +, CD7 +, CD8 +, CD45RA +, TIA-1 +, granzyme +, perforin +. CD4neg, CD30neg, CD56neg
Clonal T-cell receptor (TCR) gene rearrangement often present (usually BF-1 +)
Primary cutaneous γ–δ T-cell lymphoma
Erosion, necrosis, or ulceration common
Lichenoid or nodular pattern of atypical lymphocytes with prominent epidermotropism and frequent extension into the fat
Papillary dermal edema, and lymphocytic angiotropism and vascular destruction are common
Macrophages with phagocytosis of lymphocytes or erythrocytes (hemophagocytic syndrome) common
Lymphocytes are CD3 +, CD5 +, CD56 +, CD57neg, CD30neg, CD4neg. CD8 variable. Cytotoxic phenotype: TIA-1, granzyme, perforin positive. Epstein–Barr negative
γ–δ T-cell gene rearrangement present by definition (not α–β)
Primary cutaneous CD4 + small/medium-sized pleomorphic T-cell lymphoma
Diffuse small to medium-sized lymphocytes in dermis or subcutaneous fat, sometimes epidermis
CD3 +, CD4 +, CD8neg, CD30neg, sometimes CD7 depleted. Clonal T-cell receptor gene rearrangements may be present
Angioimmunoblastic T-cell lymphoma
Usually diagnosed from lymph node rather than skin
Diffuse lymphocytes, macrophages, eosinophils, plasma cells, and immunoblasts in the dermis
Superficial venules have prominent endothelial cells (“high endothelial venules”)
CD3 +, CD4 +, CD5 +, CXCL13 +, CD21 + (non-malignant follicular dendritic cells around vessels), CD8neg. CD10 may be positive
T-cell receptor gene rearrangements often present
Blastic plasmacytoid dendritic cell neoplasm
Diffuse lymphoid infiltrate in dermis and fat, sparing epidermis Not angiocentric (no vascular destruction), unlike other CD56 + lymphomas in 24.6 CD4 +, CD56 +, CD123 + (plasmacytoid dendritic cells), CD303 + (BDCA-2), TCL-1 +, CD3neg, CD20neg, myeloperoxidase negative (unlike myeloid leukemia). The mnemonic “123-4-56” has been used to remember the first three important staining features No clonal T-cell receptor gene rearrangement; Epstein–Barr virus negative
Primary cutaneous follicular centre lymphoma
Diffuse or nodulra lymphoid infiltrate in dermis and fat, sparing epidermis
Germinal centers with reduced mantle zones and reduced tingible body macrophages are present except in the “diffuse type”, and Ki-67 proliferation is decreased compared to normal germinal centers (see below)
CD20 +, CD79a +, Bcl-6 +. CD10 + in the follicular type (all four of these are positive outside germinal centers, with loss inside germinal centers, but not in the diffuse type). Bcl-2neg, CD5neg, CD43neg, MUM-1neg, FOX-P1neg (worse prognosis if positive). CD21 + follicular dendritic cells show an irregular network
Usually no t(14;18) translocation
Primary cutaneous marginal zone lymphoma (PCMZL)
Nodular or diffuse small lymphocytes with eosinophils and plasma cells in dermis and superficial fat, sparing epidermis
Inverse pattern of small dark reactive lymphocytes, surrounding malignant clone with increased pale cytoplasm (compared to LN)
Folliculocentric/syringotropic orientation
Reactive germinal centers present in 30%
Malignant clone positive for CD20, CD79a, bcl-2. Sometimes positive for CD23. Negative for CD43, CD5, CD10, bcl-6. Often monoclonal kappa or lambda restriction. Reactive CD3 + T cells may equal the numbers of CD20 + B cells in many cases, with only 15% of cases really having a predominance of CD20 + cells even though this is a B-cell lymphoma
Often heavy chain gene rearrangement
Translocation t(14;18) in small number of cases
Primary cutaneous diffuse large B-cell lymphoma, leg type
Dense infiltrate of large atypical lymphocytes with prominent nucleoli in the dermis
Grenz zone common but epidermotropism may be present
Adnexa often destroyed
B cells positive for CD20, CD79, MUM-1, FOX-P1, BCL-2/BCL6, sometimes CD10+
Negative for CD30 despite larger cells
J heavy chain rearrangements can be found
Other B-cell lymphomas
Epidermis usually normal without epidermotropism
Nodular or diffuse infiltrate of lymphoid cells in the dermis
Grenz zone common
Single filing of cells between collagen bundles often
Cytologic atypia and mitoses often
Cells often fragile, may show crush artifacts
Monoclonal staining common
Positive staining for B cell markers such as CD20, CD79a, PAX-5
Reactive T cells are often present
TIA-1 negative
Multiple myeloma
Diffuse plasma cells in the dermis, often atypical: multinucleated, Russell bodies, Dutcher bodies sometimes present. Mitoses prevalent
Plasma cells are CD38+, CD138+, CD56+, CD79a often positive
CD20, CD45 usually negative
Methyl green pyronin stains the cytoplasm of plasma cells red, but not commonly done
Immunostaining for kappa or lambda light chains, IgG, IgA, or IgD often reveals monoclonality
Intravascular lymphoma
Intravascular large atypical lymphocytes, often with occlusion or thrombi
Angiotropic lymphoma
Most cases are CD20+, CD79+, sometimes CD5,10,11a,bcl-2,MUM-1
CD10, EBER and bcl-6 in minority of cases
Bcl-1 negative
Pseudolymphoma
Epidermis unremarkable or often hyperplastic
Nodular or diffuse dermal infiltrate of mostly lymphocytes, also with mixed sparse or many eosinophils, macrophages, multinucleated giant cells, or plasma cells
Grenz zone, with no lymphocytes in the epidermis
Germinal centres with tingible body macrophages sometimes present
Normal germinal centres are bcl-6+ and CD1-+ with CD21+ and/or CD23+ follicular dendritic cell network
bcl-2 is negative
Endothelial hyperplasia common
Hodgkin lymphoma
Epidermis usually normal, often with a Grenz zone
Polymorphous nodular or diffuse lymphocytes in the dermis of atypical Hodgkin’s cells (CD15/30+, CD45R- TIA-1-) eosinophils, plasma cells, neutrophils, multinucleated giant cells
CD45, CD20, CD79a, PAX5, bcl-6 are variable depending on the subtype
Reed-sternberg cells are difficult to find in the rare skin lesions of Hodgkins
Leukaemia cutis
Epidermis usually normal, without epidermotropism
Nodular or diffuse cells in the dermis, often with a Grenz zone
Infiltrating cells may appear monomorphic, atypical, or immature, and often are fragile, showing crush artifacts
Single filing of cells between collagen bundles sometimes
Most leukemias will stain in the skin with the less specific stains, CD43 and CD45 (leukocyte common antigen), and are negative with most T-cell stains such as CD3 and CD45RO. Mature B-cell stains such as CD20 are negative, except sometimes it is weakly positive in CLL
Gene translocations can be identified in some leukemias, a rapidly changing area beyond the scope of this book
Mastocytosis
Perivascular or diffuse dermal mast cells, often with a few eosinophils
Dermal edema or subepidermal blister formation sometimes
Mast cells usually can be recognized with H&E stain, but are better demonstrated with Giemsa, Leder, toluidine blue, tryptase, or CD117 (c-kit). CD2 and CD25 more often positive in systemic mastocytosis with bone marrow involvement
Langerhans cell histiocytosis
Epidermis may be ulcerated
Epidermotropism of Langerhans cells into the epidermis is common
Lichenoid or diffuse dermal infiltrate of Langerhans cells (often have atypical kidney-shaped reniform nucleus), may be foamy or resemble Touton histiocytes
Polymorphous infiltrate of accompanying lymphocytes, eosinophils, neutrophils, or plasma cells often present
Positive staining of Langerhans cells for CD68, S100, CD1a, CD207 (Langerin)
Birbeck granules on EM
BRAF V600E mutations in half of all cases
Cutaneous extramedullary hematopoiesis
Bone marrow precursors of one or all three lineages may present (myeloid, erythroid, megakaryocytes), usually sparse in dermis or subcutaneous tissue (not nodular or densely diffuse)
Immature myeloid cells are CD14 +, CD34 +, CD68 +, CD117 +, and CD163 +. They also stain with Leder, lysozyme, and myeloperoxidase stains
Nucleated red blood cells (nucleated erythrocytes, normoblasts, erythroblasts) are positive for hemoglobin or glycophorin stains
Megakaryocytes are CD41 +, CD42b +, and CD61 +
Vascular or myxoid stroma
Haemangioma and vascular malformation
Epidermis normal or atrophic
Proliferation of blood vessels and endothelial cells
GLUT-1 positive in porliferating and involuting infantial haemangiomas (and placentas), negative in other vascular neoplasms, vascular malformations, non-involuting congenital haemangioma and rapidly involuting congenital haemangioma
Claudin-1 and Wilms tumour-1 (more likely to be positive in infantile haemangioma)
Angiokeratoma
Hyperkeratosis, epidermal rete ridges often encircle dilated vessels
Dilated vessels in superficial dermis, without much endothelial proliferation
Thrombi common
Pyogenic granuloma
Epidermis atrophic or ulcerated, often with crust with neutrophils (pyo-) on surface
Collarette of epidermis often demarcates the lesion
Pyogenic granuloma is a misnomer, as it is characterized by excessive granulation tissue (“proud flesh”), often arranged in vascular lobules, rather than a granuloma. Granulation tissue is vascular proliferation in a pale stroma with an inflammatory sparse or prominent infiltrate of neutrophils or lymphocytes
Angiolymphoid hyperplasia
Epidermis normal
Vascular proliferation with prominent “hobnail“ endothelial cells protruding into the lumina, often associated with vacuoles
Nodular or diffuse infiltrate of lymphocytes and eosinophils
Glomus tumour
Proliferation of blood vessels surrounded by glomus cells (monotonous cells with a dense, round nucleus and abundant pink cytoplasm), often single-filing through the stroma
Stroma often pale
Positive staining for smooth muscle actin in glomus cells. Desmin is positive in a minority of cases
Haemangiopericytoma
Epidermis normal
Cicumscribed nodule of spindle-shaped or polygonal-shaped pericytes with variable atypia
Increasing number of blood vessels, sometimes with antler-like branching (stag horn)
Reticulum stain shows that the pericytes are outside the reticulum fibres that surround the endothelium
Malignant lesions more likely to show more extravasated erythrocytes, necrosis, more cellularity, >4 mitoses per ten high-power fieldsd
Positive staining for vimentin, CD34, p75
Negative for keratin, S-100, CD31, factor VIII-related antigen, Ulex europaeus, smooth muscle actin, desmin
Angiosarcoma
Poorly demarcated dissecting blood vessels with irregular branching, papillary projections into the lumina, and sometimes slit-like spaces
Proliferating infiltrating spindled or epithelioid atypical endothelial cells. If well-differentiated, proliferating vessels may be readily identified and atypia is mild to moderate, but poorly differentiated angiosarcomas have very pleomorphic, atypical hyperchromatic endothelial cells with many mitoses, and poorly recognizable vessels
Prominent extravasated erythrocytes, sometimes hemosiderin
Reticulum stain shows endothelial cells to be surrounded by reticulum fibers
Positive staining with endothelial cell markers such as CD31, CD34, factor VIII-related antigen, ERG and FLI-1 (both newer nuclear stains), claudin-5 (newer membranous stain), and Ulex europaeus (an older stain). Ki-67 shows more positivity than benign vascular lesions. Myc nuclear staining or gene amplification is found in the majority of secondary radiation or lymphedema-associated angiosarcomas, but not in “atypical vascular proliferations” and the other primary types of angiosarcoma
Intravascular papillary endothelial hyperplasia
Within a vein or other vascular structure, numerous papillary projections of loose connective tissue proliferate, lined by many endothelial cells without atypia or mitoses
Kaposi sarcoma
Early patch-stage lesions have a subtle infiltration of the dermis by slit-like vascular spaces lined by spindled endothelial cells
In the lymphangioma-like variant, vascular spaces lack erythrocytes
In the angiomatous variant, mature, dilated, larger blood vessels may be dominant over the slit-like ones
Older lesions may have solid areas of spindle cells (mostly endothelial cells) with slit-like vascular spaces
Promontory sign sometimes present (small blood vessel and its stroma project like a promontory into a vascular space)
Cytologic atypia is usually mild, and mitoses usually sparse
Extravasated erythrocytes, occasional plasma cells, hemosiderin common
PAS positive, Mallory trichrome positive, eosinophilic hyaline globules sometimes present, which appear to represent phagocytosed erythrocyte fragments (overrated as useful)
Variable staining for vascular markers. such as CD34, which seems to work better than CD31. ERG is a new nuclear stain that works well. Ulex europaeus and factor VIII-related antigen are also positive, but utilized less commonly. Immunostaining for HHV8 is usually positive, stronger in nodules than in macules or patches, negative in other vascular proliferations
Lymphangioma
Epidermal hyperplasia sometimes
Proliferation and dilation of lymph vessels in dermis (especially papillary dermis) or deep soft tissue, lined by endothelial cells
D2-40 and Prox1 are more likely to be positive in lymphatics than in blood vessels, though they are not competely specific for this
Neurofibroma
Somewhat demarcated nodule in the dermis or subcutaneous tissue of spindle cells with wavy nuclei (diving dolphins), sometimes in strands said to resemble shredded carrots
Pale “bubblegum” pink stroma, mucinous or myxoid
Mucinous stroma stains positive for acid mucopolysaccharides
Mast cells common
Positive staining for S-100, CD34, PGP9.5, factor XIIIa, myelin basic protein, and neurofilaments. Bodian stain rarely performed, but should reveal axons (a type of neurite) since the neurofibroma is a neoplasm of the entire peripheral nerve, also including Schwann cells, endoneurial fibroblasts, and perineurial cells.
Schwannoma
Encapsulated subcutaneous tumour with cellular areas (Antoni A) and/or oedematous myxoid areas (Antoni B)
Spindle cells in Antoni A tissue line up in two parallel rows separated by an area without nuclei (Verocay bodies)
Mucinous stroma stains positive for acid mucopolysaccharides
Mast cells common
Positive staining for S-100, CD56, Calretin, myelin basic protein (Antoni A areas)
Tumour may be attached to large nerve
Neuroma
Bundles of somewhat well-delineated faciscles of peripheral nerves
Stroma often fibrotic
Positive staining for S-100, myelin basic protein, and neurofilaments
Granular cell tumour
Epidermal hyperplasia, sometimes pseudoepitheliomatous hyperplasia
Infiltration of the dermis or subcutaneous tissue by large cells with a granular cytoplasm and small centrally located nuclei
Larger eosinophilic intracytoplasmic granules are called pustulo-ovoid bodies of Milian
Granules are positive with PAS stain or PTAH but usually negative with lipid stains
Tumour stains positive for myelin basic protein, NSE, calretin, S-100, NKI-C3, CD68
Heterotopic neuroglial tissue
Epidermis atrophic
Atrocytes and neurons in a pale neurofibrillary stroma
Multinucleated giant cells common
Calcification sometimes
Fibrotic stroma, vascular ectasia common
Glial fibrillary acid protein stains glial cells, neuron-specific enolase stains the neurons
Bodian silver stain or neurofilament stain demonstrates neurites (axons) extending from neurons
Heterotopic meningeal tissue
Sharply demarcated connection throguh skull to central nervous system
Meningothelial cells are epithelioid or spindled, with vesicular nuclei abundant pink cytoplasm with indistinct borders, often in a hyalinised stroma. Wide variation in patterns. Usually no cytologic atypia and no mitoses unless anaplastic
Pseudovascular spaces sometimes, dense fibrous stroma often
Minengothelial whorls and psammoma bodies sometimes present
Positive staining for vimentin and epithelial membrane antigen and claudin-1 in meningothelial cells with variable staining for S-100, neuron-specific enolase and cytokeratin
Myxoid neurothekeoma
Pale myxoid sharply demarcated or encapsulated dermal or subcutaneous nodule divided into lobules or fascicles by fibrous septa
Spindle cell nuclei may be pleomorphic, sometimes epithelioid
Mucinous stroma stains positive for acid mucopolysaccharides
Positive staining for S-100, GFAP, type IV collagen, weak for NSE; negative for
axons (neurofilament immunostain or Bodian stain), EMA, keratin
Merkel cell carcinoma
Diffuse dermal atypical small blue cells with minimal cytoplasm, in clusters, rosettes, and cords (trabeculae) in the dermis, usually with many mitoses
Epidermotropism of the small cells, or coexisting bowenoid change may be present
Positive staining often with neuron-specific enolase (NSE), epithelial membrane antigen (EMA), CD56, neurofilament, synaptophysin, chromogranin, or argyrophil stains. There is often a classic paranuclear dot staining patternwith low molecular weight keratin, such as CK20, cam 5.2, AE-1. Negative staining for S-100, TTF-1, CK5/6, CEA, and LCA. Some rare CK20neg cases will stain with CK7, but CK7 is usually negative. Bombesin may be positive in Merkel cell carcinoma, but some studies found it to be negative and more likely positive in metastatic neuroendocrine carcinoma in the skin, so it is mainly used as an old exam question and not in clinical use. CM2B4 stains the large T-antigen of the polyoma virus, and is highly specific for MCC but not sensitive (only 60% of MCCs are positive). P63 positivity is said to indicate poor prognosis and bcl-2 a favorable prognosis
Malignant peripheral nerve sheath tumor
Poor circumscription of mass
Proliferation of spindle cells with wavy nuclei in a pale mucinous stroma
Often p75 +, CD56 +, PGP9.5 +, and nestin +. Sometimes weakly S-100 +. Ki-67 often positive in ≥ 20% of cells, Sox10131 may be positive, but some authorities say this is more common in benign cellular schwannomas. Loss of INI-1 (SMARCB1) in 50% of cases (more commonly lost in epithelioid sarcoma, 27.14). H3K27me3 staining is lost in 70% of cases, but not in melanomas, synovial sarcomas, and myoepithelial tumors.
Cytologic atypia (pleomorphism, hyperchromatism, increased numbers of mitoses) often present, but not always prominent
Necrosis sometimes present
Malignant transformation of neurofibroma in NF1
Dermatofibroma
Epidermal hyperplasia often, sometimes with flattenede ‘tabled’ rete ridges or basaloid proliferatoin simulating a basal cell carcinoma
Hyperpigmented basal layer often
Poorly circumscribed proliferation of boomerang-shaped spindled fibroblasts or histiocytes in the dermis, often whorling about, blending into the surrounding dermis like a bomb that was dropped in the dermis, sometimes extending into the subcutaneous fat
Multinucleated giant cells, Touton giant cells, foamy histiocytes sometimes
Haemosiderin often
Large bundles of collagen (keloidal collagen) often at the periphery
Positive for CD68, CD163, Factor XIIIa
Negative for CD34
Scar
Epidermis atrophic or normal, often with loss of rete ridges
Subepidermal blister artifact is common
Bands of fibroblasts and dense collagen, often oriented parallel to the
epidermis
Young scars may have a pale or mucinous stroma and more fibroblasts, sometimes extravasated erythrocytes, while older ones have more collagen, less paleness, and fewer fibroblasts (more sclerotic)
Blood vessels tend to be more perpendicularly oriented with respect to the epidermis
Angiofibroma
Collagen oriented concentrically around follicles or oriented more perpendicular to the epidermis
Sometimes increased numbers of stellate, plump fibroblasts
Few dilated blood vessels
TSC
Familial myxovascular fibromas
Multiple endocrine neoplasia type 1
Acrochordon
Pedunculated papule, epidermis often extends almost completely around the specimen when it is sectioned
Papillomatosis and acanthosis common, sometimes epidermal atrophy
Dermis consists of loose connective tissue that is often pale
Dilated blood vessels often
Acquired digital fibrokeratoma
Massive orthokeratosis, usually no parakeratosis, with acanthosis
Thickened collagen in the dermis, often oriented parallel to the long axis of the lesion
Connective tissue naevus
Poorly demarcated nodule with increased collagen and normal, decreased or increased elastic fibres
Sometimes easily missed
Shagreen patch of TSC (no increase in elastic tissue) Naevus elasticus (increased elastic tissue) Buschke-ollendorff syndrome
Infantile digital fibromatosis
Dense band of collagen and many plump myofibroblasts
Eosinophilic cytoplasmic inclusion bodies (3-10 microns) in the myofibroblasts, often adjacent to the nuclei
Easier seen with PTAH, actin or trichrome stains, negative with PAS
Nodular fasciitis
Subcutaneous somewhat circumscribed nodular proliferation of myofibroblasts in a loose, mucinous stroma, resembling “tissue-culture fibroblasts”
Muscle-specific actin or smooth muscle actin often positive, but desmin is usually negative. Vimentin and CD68 positive. S100, caldesmon, and CD34 are negative
Sometimes infiltration through muscle or along fibrous septa of fat
Fibroblasts may be moderately pleomorphic, hyperchromatic, or may show
increased mitoses that are not atypical
Multinucleated osteoclast-like giant cells may be present
Often prominent vascularity, sometimes slit-like spaces, extravasated
erythrocytes
Lymphocytes often present within the nodule to a greater extent than usual in
a sarcoma, especially at the margin
Giant cell tumour of tendon sheath
Sharply demarcated localized lobule
Proliferation of fibroblasts and histiocytes, sometimes foamy
Large osteoclast-like giant cells with many haphazard nuclei usually
present
Hemosiderin often present
Dermatofibrosarcoma protuberans
Epidermis normal, atrophic, or ulcerated (rarely hyperplastic)
Very cellullar proliferation of thin spindled fibroblasts and collagen in the dermis, extending into the subcutaneous fat
Cartwheel pattern (fibroblasts whorl around like spokes of a wheel) or storiform (whirligig or mat-like) pattern
Usually no foamy cells or multinucleated giant cells, unlike dermatofibroma
Infiltration of fat in a fascicular or honeycomb pattern
Mast cell counts are less frequent in tumours that have more mitoses or larger size
Cytologic atypia mild to moderate, very few mitoses
CD34 +, nestin +, stromelysin-3-neg, factor XIIIa-neg, D2-40-neg (all five opposite of dermatofibroma)
S-100 and SOX10 are negative
Pleomorphic sarcoma
Subcutaneous cellular proliferation of fibroblasts, histiocyte-like cells, and bizarre giant cells
Severe pleomorphism, hyperchromatism, many bizarre cells or highly atypical mitoses often
Vimentin +: variable positivity with fibrohistiocytic markers CD68, alpha-1 antitrypsin, and alpha-1-antichymotrypsin. Variable positivity with muscle markers desmin and actin. CD34 is negative.
Atypical fibroxanthoma
Dermal cellular proliferation of bizarre spindle cells, epithelioid cells, or multinucleated giant cells, and sometimes foamy cells (hence the name xanthomatous, but it frequently does not have this feature), often extending up against the epidermis
Severe pleomorphism, hyperchromatism, many very atypical mitoses
Solar elastosis
Positive staining for vimentin, CD68, S100A6, antichymotrypsin, antitrypsin, procollagen-1, and strongly positive for CD10. CD99 positive in 70%. Sometimes calponin, SMA or desmin positive in minority of cases. EMA may be focally positive. CD163 is more specific for histiocytes than CD68, but positivity for CD163 varies in studies of AFX. Negative for CD31, CD34, S-100 (except few dermal dendrocytes), pankeratin, SOX10, p40, and p63, with few exceptions.
Variants with granular cells, osteoclastic giant cells, myofibroblastic cells, CD30 + lymphomatoid cells, or with keloidal, chondroid or bony areas have been described
Fibrosarcoma
Subcutaneous densely cellular proliferation of uniform spindle cells, sometimes with a herringbone pattern (nuclei radiate off on either side of a central “vertebral” column)
Cytologic atypia mild to moderate, depending upon how well differentiated it is. Necrosis and mitoses common
Vimentin +. Negative staining for pankeratin, S100, CD34, desmin, SMA
Epithelioid sarcoma
Poorly circumscribed often ulcerated proliferation of polygonal atypical epithelioid cells and spindled cells, often palisade around central necrosis, resembling a palisading granuloma
Pleomorphism, hyperchromatism, numerous mitoses
Lymphocytes common, especially at tumor periphery
Positive staining with both pankeratin and vimentin (hence the tumor’s name, which refers to epithelial-like staining with keratin, as well as sarcomatous staining with vimentin). EMA is also positive. ERG and FLI-1 positive in 60–70%. D2-40 + in 60% and CD34 + in 50% of cases. Loss of INI-1 (SMARCB1) expression in 90%; this loss also found in half of cases of malignant peripheral nerve sheath tumor (26.9).
Fibromatosis
Dense hyalinized collagenous neoplasm with poorly defined borders
Scattered fibroblasts, sometimes with corkscrew nuclei (may be more cellular in early lesions) without atypia or mitoses
Nuclear staining for beta-catenin is usually found in fibromatosis, but negative in fibrohistiocytic tumors or sarcomas
Calcifying aponeurotic fibroma
Spindle or epithelioid fibroblasts tend to palisade around areas of dense collagen and calcification
Cartilage may form in the calcified areas in older lesions
Myxoma
Poorly demarcated, paucicellular nodule of vimentin + stellate spindle cells in vascular myxoid stroma. Occasionally multinucleated cells may be present
Variable staining for S100, CD34, factor XIIIa, SMA, MSA. Desmin is negative
Often contains epithelial strands, cysts, or trichoblastic changes
Minimal cytologic atypia, but mitoses may be present
Plexiform fibrohistiocytic tumour
Fascicles of spindle or epithelioid cells in complex plexiform pattern
Nodular aggregates of CD68 +, SMA + histiocytes, multinucleated giant cells , and lymphocytes, suggesting granulomas seen in an infectious process
Mild to absent pleomorphism, mitoses rare
Extravasated erythrocytes and hemosiderin often
May contain myofibroblasts positive for actin
Fibrous hamartoma of infancy
Ill-defined subcutaneous nodule with three components: whorled cellular islands of round or spindle cells in a myxoid stroma, hypocellular fibrous fascicles, and islands of adipose tissue
Solitary fibrous tumour
Spindle cell nodule said to have a “patternless pattern.”
Slit-like staghorn vascular channels
Immunoprofile is vimentin +. CD34 + in 90% and CD99 + in 70% of cases. S100, EMA, and actin sometimes positive. Staining is negative for factor XIIIa. Characteristically positive nuclear staining for STAT-6 (a surrogate stain for the NAB2-STAT6 fusion gene that is relatively specific for this tumor), and has a more benign course than DFSP despite being CD34 +
Cutaneous PEComa
Clear cells within a dermal nodule, accentuated in perivascular distribution
Immunoprofile may suggest a melanocytic tumour, except that S100 is negative
HMB-45, MiTF, NKI-C3, PAS (glycogen) are positiev. MART-1, desmin and CD68 are variable. SMA, pankeratin, and EMA are negative
TSC1/TSC2 mutatinos are common, less common is TFE3 gene rearrangements
Metastatic squamous cell carcinoma
Dermal tumour with features of SCC, keratin pearls/squamous eddies if well differentiated with no connection to the epidermis
Pleomorphism and hyperchromatic nuclei, increased numbers of mitoses, more prominent if poorly differentiated
Usually not possible to determine the site of origin of the tumour based upon histologic features
Pseudoglandular spaces without mucin may be due to acantholysis
Positive staining for pankeratin, CK5/6, other keratins
p40 and p63 usually positive
Metastatic adenocarcinoma
Tumour in the dermis with variable small glandular formations or signet-ring cells
Pleomorphism, hyperchromatism, increased number of mitoses
Mucin stains stains mucin
Site usually not possible to determine but sometimes staining can be helpful
CK7, CK20 (colon CK20+, CK7-; lung usually CK7+, CK20-; breast/ovarian CK7+m prostate CK7-)
Metastatic breast carcinoma
Tumour nodules or single-filing strands with pleomorphic, hyperchromatic nuclei, increased numbers of mitoses in the dermis or in the lymphatics or blood vessels. Nuclei sometimes appear somewhat square or rectangular, lined up like vertebral body-like structures
Epidermotropism may occur as in Paget’s disease
Glandular formation or “signet” rings sometimes present, may contain mucin
+ pankeratin, CK7, GCDFP, mammaglobin, androgen receptor, Sox10/S100
- CK20 usually
Her-2 staining poor prognosis
GATA3, low expression poor prognosis
Metastatic renal cell carcinoma
Tumour lobules in the dermis, often surrounded by epidermal collarette
Large clear cells (containing glycogen and lipid) with central nuclei that usually are only mildly atypical
Vascular stroma, often with extravasation of erythrocytes and haemosiderin
Positive staining for both
Metastatic small cell carcinoma
Diffuse infiltration of the dermis by nodules or cords of cells with atypical small round nuclei and little cytoplasm, often increased number of mitoses
Metastatic sarcoma
Spindle cell infiltration of the dermis in most cases, although sometimes can be epithelioid
Positive staining for vimentin, with negative staining for pankeratin in most cases
Naevus lipomatosus
Adipose present in superficial dermis
Increased dermal blood vessels often
Lipoma
Proliferation of normal-appearing adipose in the subcutaneous fat
Sometimes sharp demarcation (rarely a capsule) from normal adipose
Benign lipoblastoma
Subcutaneous tumour (poorly circumscribed or encapsulated) of immature fat cells with lipoblasts (lipid vacuoles displace the nuclei)
Mucinous stroma
Hibernoma
Subcutaneous encapsulated tumour of mulberry cells (large cells with a central nucleus and multivacuolated granular cytoplasm), sometimes mixed with mature adipocytes
Liposarcoma
Tumour in subcutaneous fat or soft tissue consisting of cells containing lipid with variable differentation toward adipose tissue
Lipoblasts (cells with several lipid vacuoles displacing the nuclei) or signet-ring cells (single lipid vacuole displacing the nucleus)]
S-100 protein, calretin sometimes positive
Molecular studies can be performed such as FISH, CGH, qPCR
Leiomyoma
Proliferation of benign smooth muscle bundles, with blunt ended cigar-shaped spindle cell nuclei and abundant pink cytoplasm on longitudinal section and round nuclei with vacuoles around them on cross-section
Positive red staining with trichrome and immunostaining with desmin, muscle-specific actin, or smooth muscle actin
Reed syndrome
Leiomyosarcoma
Smooth muscle proliferation
Atypical pleomorphic nuclei with hyperchromatism, increased numbers of mitoses, necrosis
Desmin, muscle specific actin, calponin, caldesmon, HHF35, S100/CK uncommonly positive
Myofibrils can be identified with PTAH stain
Osteoma cutis
Eosinophilic bony tissue in the dermis or subcutaneous fat, osteocytes (within lacunae) usually present, osteoclasts (multinucleated cells) sometimes present, osteoblasts sometimes present, distinct trabeculae sometimes present
Calcification may be present
Haemopoiesis is rarely present within the bone
Albright’s hereditary osteodystrophy
Gardners syndrome
Naevus of Nanta
Cutaneous endometriosis
Endometrial glands, straight or tortuous, lined by a pseudostratified columnar epithelium with active secretion resembling apocrine glands
CD10+, atypical fibrovascular myxoid stroma
Extravasated erthrocytes and haemosiderin common
Accessory tragus
Pedunculated papule or nodule containing numerous vellus hair follicles and often cartilage
Omphalomesenteric duct polyp
Ectopic gastric, small intestinal or colonic intestinal epithelium with goblet cells present within eroded periumbilical skin
Diffuse lymphocytes common in the stroma
Accessory nipple
Epidermis with mild papillomatosis and hyperpigmentation
Increased smooth muscle bundles
Mammary glands and ducts present in dermis and subcutaneous fat
Pityriasis Alba
Focal parakeratosis
Focal spongiosis
Perivascular lymphocytes
