Skin-nontumor - Printer Friendly Version
Last revised 25 April 2007
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Bold and underlined topics are hypertext links within this document or to references
Primary references, skin-general, histology-epidermis, adnexae, dermis, subcutaneous, biopsies, grossing, common pathologic terms
Infectious disorders: abscess, anthrax, carbuncle, CMV, Epstein-Barr virus, erysipelas, Erysipelothrix, folliculitis, fungi (various), hepatitis C, herpes simplex/zoster, hidradenitis suppurativa, histoplasma, HIV, impetigo Leishmaniasis, leprosy, Lyme disease, malakoplakia, molluscum contagiosum, mycobacteria-atypical, parvovirus, prototheca, scrub typhus, smallpox vaccination, syphilis, tuberculosis, tularemia, virus associated trichodysplasia spinulosa, warts
Infestations: general, body louse, botfly, brown recluse spider, demodex, pediculosis (lice), pubic louse, scabies, Tunga penetrans
Granulomatous but noninfectious disorders: arthropod bites, foreign body reaction, interstitial granulomatous dermatitis, interstitial granulomatous drug reaction, sarcoidosis
Blistering disorders: general, blood blister, bullous impetigo, bullous pemphigoid, cicatricial pemphigoid, Darier’s disease, dermatitis herpetiformis, epidermolysis bullosa, epidermolytic hyperkeratosis, erythema multiforme, erythema toxicum neonatorum, Hailey-Hailey, herpes gestationis, impetigo contagiosa, linear IgA disease, pemphigus, porphyria, Stevens-Johnson syndrome, subcorneal pustular dermatosis, transient acantholytic dermatosis
Other dermatoses: acanthosis nigricans, acne rosacea, acne vulgaris, acute eczematous dermatitis, allergic contact dermatitis, alopecia mucinosa, alpha-1-antitrypsin deficiency panniculitis, amyloidosis, anetoderma, annular elastolytic giant cell granuloma, argyria, arsenic, Behcet’s disease, calciphylaxis, chondrodermatitis nodularis, chronic skin ulcer, Crohn’s, cytophagic histiocytic panniculitis, dermatomyositis, drug reaction, elastosis perforans, eosinophilic fasciitis, eosinophilic pustular folliculitis, erythema elevatum diutinum, erythema nodosum, exfoliative dermatitis/erythroderma, gangrene, graft versus host disease, granuloma annulare, granuloma faciale, gyrate erythema, hemochromatosis, ichthyosis, irritant contact dermatitis, lichen nitidus, lichen planus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen striatus, lichenoid dermatitis, lipogranulomatosis, lupus erythematosus, malignant atrophic papulosis, massive localized lymphedema, mastocytosis of skin, metabolic abnormalities, miliaria, mucinoses, myxedema, necrobiosis lipoidica, necrobiotic xanthogranuloma, ochronosis, pancreatic fat necrosis, panniculitis, pityriasis lichenoides chronica, pityriasis lichenoides et varioliformis acuta, pityriasis rosea, pityriasis rubra pilaris, polymorphous light eruption, prurigoform acanthosis, pseudoxanthoma elasticum, psoriasis, pyoderma gangrenosum, radiation-associated, rheumatoid/rheumatic nodules, scleredema, scleroderma, seborrheic dermatitis, segmented hyalinizing vasculitis, skin graft rejection, spongiotic dermatitis, stasis dermatitis, subcutaneous fat necrosis of newborn, Sweet’s syndrome, synovial metaplasia, tattoo, urticaria, vasculitis, Weber-Christian disease
Go to Skin-tumor chapter/outline
American Journal of Surgical Pathology (AJSP), January 2000 to May 2005
Archives of Pathology and Laboratory Medicine (Archives), January 1999 to May 2005
Human Pathology (Hum Path), Jan 2000 to March 2005
Modern Pathology (Mod Path), Jan 2000 to April 2005
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Journal search terms: skin, epidermis, dermis, cutaneous
Please refer to these primary references for more detailed discussions and photographs
Also called integument
Protects deeper tissues from injury, drying and invasion by foreign organisms
Contains peripheral endings of sensory nerves
Has important role in thermoregulation, limited role in excretion and absorption
Has epidermis (cuticle) containing adnexae, underlying dermis and subcutis
Epidermis is outer layer of skin; inner layers are dermis and subcutaneous tissue; superficial fascia marks deep boundary between skin and underlying soft tissue
Epidermis forms outer layer of keratin that is protective and waterproof
Thicker in palms and soles, which contain epidermal ridges that prevent slipping and comprise fingerprints and footprints
Stratified squamous epithelium composed of keratinocytes in 4 layers: inner basal, squamous, granular and outer cornified
Basal layer: mitotically active, produces other keratinocytes; contains low molecular weight keratin; separated from dermis by continuous basal membrane, keratinocytes are attached to this membrane by hemidesmosomes; also contains melanocytes
Squamous layer (stratum spinosum): also called prickle or malpighian layer; several layers of cells, larger than basal layer, become flat and eosinophilic as they approach the surface due to an increase in keratin component and reduction in ribosomes; may have clear vacuolated cytoplasm; cells are attached to each other by fine spiny bridges, with central dot-like desmosomes (Bizzozero’s nodule); loss of spiny bridges causes acantholysis
Granular layer (stratum granulosum): 1-3 layers of flattened cells with intensely basophilic keratohyaline granules, which contain precursors of filaggrin protein, which causes aggregation of keratin filaments
Stratum lucidum: present only in soles and palms, between granular and cornified layer; homogenous eosinophilic zone
Cornified layer (stratum corneum): also called horny layer; basket weave pattern of multiple layers of polyhedral cells without nuclei (region is thicker and more compact in acral region [peripheral body-limbs, fingers, ears])
Rete ridges: undulating forms of epidermis and dermal papillae at dermoepidermal junction; flatten with aging
Keratinization: takes 30-45 days; alterations in pattern and speed cause dermatoses, hyperkeratosis or parakeratosis
Cells present include melanocytes, keratinocytes, Langerhans’ cells, Merkel cells
Melanocytes
Neural crest origin; in basal epidermis, hair follicles, most squamous mucous membranes, leptomeninges; produce melanin from tyrosine, transfer it (via cytocrinia) to adjacent epithelial cells, to protect against ultraviolet rays; have frequency of 10-25% of keratinocytes; racial skin color is due to amount of melanin in keratinocytes, not number of melanocytes; contain dendrites (delicate cytoplasmic processes that extend between keratinocytes); upwards or lateral migration within epidermis or into papillary dermis does not necessarily indicate malignancy; cytoplasm is clear due to retraction, nuclei typically smaller and slightly more hyperchromatic than nuclei of adjacent keratinocytes, have uniform chromatin, indented nuclear contour, no nucleoli
Positive stains: Fontana-Masson, tyrosinase, S100, NSE, MelanA/Mart1, microphthalmia transcription factor, vimentin, bcl2, HMB45 (activated melanocytes), variable keratin in activated melanocytes
Negative stains: GFAP, neurofilament, HMB45 and keratin (resting melanocytes)
EM: melanosomes (melanin-synthesizing organelle derived from Golgi)
DD: melanoblasts (immature counterpart), melanophages (macrophages with ingested melanin)
Langerhans’ cells
Bone marrow derived dendritic cells that present antigens to T cells, are scattered in upper squamous layer but difficult to see on H&E; have characteristic Birbeck granules by EM (rod shaped structure with zipper-like striations, often with bulbous end), S100+, CD1a+, IgG Fc receptor+, C3+
Merkel cells
Difficult to see with H&E or special stains; concentrated in skin of digits, lips, outer root sheath of hair follicles, tactile hair disks; EM shows dense core neurosecretory-type granules in cytoplasm beneath cell membrane or within unmyelinated neurites; anchored to adjacent keratinocytes by spinous processes; positive for NSE, neurofilament, keratin
Skin adnexa include hair follicles, sebaceous glands, eccrine sweat glands, apocrine glands
Pilar unit: functional complex of hair follicle, sebaceous gland, erector pili muscle and (depending on site) apocrine gland; often contains Demodex folliculorum mites, clumps of Staphylococcus epidermidis, Pityrosporum yeasts
Hair follicle: contains protected repositories of epithelial stem cells; forms hair via cyclic process of (a) anagen or growing phase, (b) catagen or involuting phase and (c) telogen or resting phase
Matrix (regenerative) cells line dermal papillae, are mitotically active, give rise to hair shaft and inner root sheath
Outer root sheath: layer of large cells that surround inner root sheath, undergo abrupt keratinization without a granular layer, at level of isthmus (mid hair follicle, extends to sebaceous duct), called trichilemmal keratinization
Usual type of keratinization occurs by cells of infundibulum (upper hair follicle)
Acrotrichium: intraepidermal portion of hair follicle
Sebaceous glands: lobulated structures, have outer germinative cells that differentiate, move inward and accumulate intracytoplasmic lipid droplets, causing multivacuolation and multiple indentations of nuclei; excretory duct of these glands empty into infundibulum of hair follicle
Sweat glands are either eccrine (regulate body temperature), apocrine or mixed
Eccrine sweat glands: tubular with secretory and excretory portions; secretory coil is in deep dermis or subcutis, has secretory and myoepithelial cells; excretory portion has dermal (straight) and intraepidermal (spiral, also called acrosyringium) portions
Apocrine glands: concentrated in axilla, groin, perineum; also face and elsewhere; have secretory and excretory components; epithelial cells are larger than eccrine glands with larger ducts and decapitation secretion; secretory cells have abundant eosinophilic cytoplasm with lipid, iron or lipofuscin; positive for GCDFP-15
Positive stains: eccrine and apocrine glands - EMA, CEA, keratin, S100; myoepithelial cells - actin, calponin, caldesmon, S100
Contains collagen and elastic fibers in ground substance of mucopolysaccharides and mucoproteins
Also contains adnexa, nerves and blood vessels
Degenerates with age and sunlight and becomes basophilic
Divided into the superficial adventitial dermis and deeper reticular dermis
Adventitial dermis is divided into papillary dermis containing rete pegs and periadnexal dermis
Adventitial dermis has thin and delicate collagen fibers versus thicker fibers in reticular dermis
Dermis has varying thickness - thicker on back
Acral skin has Sucquet-Hoyel canals – specialized arteriovenous anastomoses, surrounded by glomus cells
Glomus cells are modified smooth muscle cells but round with clear cytoplasm and well defined cytoplasmic borders
Papillary dermis of palms and soles contains Wagner-Meissner corpuscles with a tactile function
Deep dermis and subcutis of weight bearing areas contain Pacinian corpuscles, sensitive to pressure
Normal dermis contains a few fibroblasts, mast cells, macrophages, lymphocytes and dermal dendrocytes (factor XIIIa+)
Histology - Subcutaneous tissue
Also called subcutis
Contains lobules of mature adipose tissue and thin connective tissue septa
For inflammatory lesions, should correlate with clinical differential diagnosis
Biopsy characteristic areas, not ruptured bullae, secondarily infected / scratched areas or involuting lesions
Punch biopsy of nearby normal skin may be helpful, particularly if changes in abnormal areas are quantitative (hyperkeratosis, acanthosis, etc.)
Must recognize that biopsy captures histopathology only at one point in time in evolution of a lesion
EM of axillary skin biopsy may be helpful to diagnose metabolic abnormalities, although results may be nonspecific (Hum Path 2001;32:649)
Breadloafing (serial section) of ellipses is often best – cut perpendicular to long axis at 3 mm intervals
Always ink margins
Bisect punch biopsies if 4 mm or larger
Acantholysis: loss of intercellular connections (desmosomes) between keratinocytes; occurs in pemphigus vulgaris and related disorders; causes change in cell shape from polygonal to round
Acanthosis: thickening of epidermis (squamous layer), rete ridges usually extend deeper into dermis
Atrophy: thinning of epidermis, associated with age or disease
Basophilic degeneration: age and sunlight related changes of collagen and elastic fibers Blister: vesicle or bullae
Bullae: fluid filled area > 5 mm; intraepidermal or subepidermal; intraepidermal bullae are due to spongiosis or acantholysis; subepidermal bullae are due to extensive papillary dermal edema
Colloid bodies: also called Civatte bodies; apoptotic keratinocytes, oval/round, immediately above or below epidermal basement membrane
Dyskeratosis: abnormal, premature keratinization of keratinocytes below granular cell layer; often have brightly eosinophilic cytoplasm
Epidermolysis: alteration of granular layer with perinuclear clear spaces, swollen and irregular keratohyalin granules, increased thickness of granular layer; different from acantholysis
Epidermotropism: atypical lymphocytes present in epidermis (seen in cutaneous T cell lymphoma)
Erosion: discontinuity of skin causing partial loss of epidermis (compare to ulceration)
Excoriation: deep linear scratch, often self-induced
Exocytosis: nromal appearing lymphocytes in epidermis (spongiotic dematitis)
Hydropic (liquefactive) degeneration: basal cells become vacuolated, separated and disorganized
Hyperkeratosis: thickened cornified layer, often with prominent granular layer; keratin may be abnormal; orthokeratotic hyperkeratosis is exaggeration of normal pattern of keratinization (no nuclei in cornified layer); parakeratotic hyperkeratosis has retained nuclei in cornified layer
Lentiginous: linear pattern of melanocytic proliferation within epidermal basal cell layer
Leukocytoclasis: karyorrhexis and destruction of neutrophils; occurs with neutrophilic vasculitis (also called leukocytoclastic vasculitis)
Lichenification: thick, rough skin with prominent skin markings usually due to repeated rubbing
Lichenoid interface change: destruction of basal keratinocytes, causing remodeling of basement membrane zone; also bandlike lymphocytic infiltrate
Macule: circumscribed flat colored area of any size
Nodule: deeply extending papule > 5 mm
Oncholysis: loss of integrity of nail substance
Papillomatosis: outward overgrowth of epidermis with elongation of dermal papillae
Papule: elevated and solid area, 5 mm or less
Parakeratosis: cells of cornified layer retain their nuclei, often less prominent or absent granular layer; normal for mucous membranes
Patch: large macule
Plaque: elevated flat topped area, usually > 5 mm
Pustule: intraepidermal or subepidermal vesicle or bullae filled with neutrophils
Scale: dry, horny, platelike excrescence usually due to imperfect cornification
Scale crust: parakeratotic debris, degenerating inflammatory cells and tissue exudate on surface of epidermis
Spongiosis: intraepidermal edema, causing splaying apart of keratinocytes in stratum spinosum (resembling a sponge), vesicles due to shearing of desmosomes
Ulceration: discontinuity of skin causing complete loss of epidermis and possible loss of dermis
Vesicle: fluid filed area, 5 mm or less
Wheal: itchy, transient, elevated area with variable blanching and erythema, due to dermal edema
Infectious disorders
“Coal” in Greek; refers to black coloration of skin eschar
Due to endospores of Bacillus anthracis, a common soil organism
Causes cutaneous, pulmonary or gastrointestinal symptoms
Culture: nonhemolytic, nonmotile, ground-glass colonies that retain their shape when manipulated; grow readily on sheep red blood cell agar (no special conditions needed)
Gram stain: gram positive, spore-forming rods
Treatment: antibiotics, reduces mortality from 20% to less than 1%
Case reports: 51 year old woman with localized skin ulceration and prominent edema of forehead, culture negative for B. anthracis (Archives 2004;128:709)
Micro: eschar shows coagulative necrosis of superificial
epidermis and dermis, with prominent edema of underlying viable dermis,
frequent focal hemorrhages, intense, reactive-appearing mononuclear
inflammatory infiltrates around small vessels and some adnexae; neutrophils
only around necrotizing sebaceous glands; sharp demarcation between superficial
necrotic and deeper edematous viable tissue (at periphery), occasional islands
of regenerating epidermis under necrotic layer of eschar; vessels with
degenerated endothelial cells and focal thrombi; no abscess; no granulation
tissue
References: slide show; Centers for Disease Control
Painful localized bacterial infection of skin and subcutis, usually with several openings through which pus is discharged
Ubiquitous virus in humans, usually infection by early adulthood
Primary EBV infections are asymptomatic or may cause infectious mononucleosis; Japanese or other Asians may develop chronic infections
Chronic active EBV infection: chronic recurrent infectious mononucleosis-like symptoms, has high mortality due to virus-associated hemophagocytic syndrome, NK/T cell lymphomas, EBV related cardiovascular disease and large vessel arteritis; also hypersensitivity to mosquito bytes in 1/3 (may be initial symptom), causing necrotic skin ulceration and scarring
Case reports: 11 year old Japanese-Filipino girl with chronic active EBV infection and mosquito byte hypersensitivity, leading to EBV+, NK/T cell lymphoma (Hum Path 2005;36:212)
Streptococcal infection causing upper dermal edema and “orange peel” or peau d’orange appearance
Erysipelothrix rhusiopathiae is an animal bacteria that rarely causes cutaneous disease in humans that work with animals or fish
Causes cutaneous erysipeloid and rarely endocarditis of aortic and mitral valves
Insidious onset over months
May cause botryomycosis, a pseudomycosis due to nonfilamentous bacteria with characteristic hyaline granules
Case reports: 54 year old black man with fatal endocarditis, no skin lesions, no history of animal/fish exposure (Hum Path 2005;36:117)
Micro: slender or filamentous gram positive rod similar to actinomycetes
Inflammation around hair follicles, involving follicular opening or adjacent skin
Infectious cases are either superficial (fungi, bacteria, syphilis, viral) or deep (granulomatous, due to fungi or bacteria)
Fungal forms may be endothrix (spores within hair shaft) or ectothrix (spores on outer surface of hair shaft)
Noninfectious cases are superficial/suppurative (acne vulgaris, rosacea, follicular mucinosis, steroid-induced), deep/granulomatous (acne vulgaris-conglobate and keloidal forms or perforating) or spongiotic (Fox-Fordyce disease, atopic dermatitis, pruritic folliculitis of pregnancy)
Perifolliculitis forms are either primarily lymphocytic (lichen planopilaris, pityriasis rubra pilaris) or granulomatous (perioral dermatitis, rosacea)
Pseudolymphomatous folliculitis: facial lesion with dense, polymorphic, mixed lymphocytes around hair follicles and infiltrating follicular epithelium
Fungi-Candida
Fungi-Chromoblastomycosis
Clinically resembles carcinoma; color of lesion is due to brown spores
Indolent cutaneous disease due to Phialophora, Fonsecaea or Cladosporium fungi, that multiply by cross wall formation and splitting
Cultures (Phialophora): slow growing, dark gray-black and hairlike
Gross: verrucous or nodular, resembling carcinoma
Micro: marked pseudoepitheliomatous hyperplasia and mixed granulomatous-neutrophilic infiltrate; contains brown spores; fungi have cross walls but no budding
DD: Blastomyces dermatitis (budding, double contoured)
References: more information and images
Fungi-Histoplasma capsulatum
A dimorphic saprophytic fungus found in soil contaminated with bird or bat feces
Endemic to southeast US (80% of this population may have positive intradermal histoplasmin skin test), Mexico, Africa, Asia
Infection is via inhalation of spores, causing a primary pulmonary pneumonia
Pneumonia is self-limited in immunocompetent patients, but disseminates in immunocompromised (very young, very old, HIV+) to liver, spleen, bone marrow, nodes, lung, rarely to skin
Disseminated disease: strongly associated with AIDS; fever, weight loss, splenomegaly; variable cutaneous lesions
Culture: tan-white-brown wooly mold at 25-30C on Sabouraud dextrose agar; organisms have delicate, septate hyphae, 1-2 microns thick, with large rough-walled macroconidia 5-15 microns; revert to yeast at 37C on sheep blood agar; yeast is 2-4 microns, budding, single nuclei, round/oval with thin rigid walls
Treatment: antifungal drugs
Case reports: 27 year old woman with multiple cutaneous lesions (Archives 2004;128:e15), 33 year old HIV+ man with recurrent disseminated disease (Archives 2001;125:571); atypical variant causing disseminated cutaneous disease in healthy 5 year old (Rev Inst Med trop S Paulo;1999:41:195); 38 year old man with AIDS, skin lesions and fever
Gross: cutaneous lesions are nodules, papules, ulcers; less commonly macules, pustules or vesicles
Micro: isolated intracellular organisms, larger aggregates surrounded by chronic inflammatory cells and fibroblasts (but no neutrophils or eosinophils) or epithelioid granulomas with variable caseation; may be narrow based budding of spores
Positive stains: PAS, GMS
References: more information #1; #2
Fungi-North American blastomycosis
Skin lesions usually secondary to pulmonary blastomycosis; rarely occur at site of penetrating injuries
Due to Blastomyces dermatitidis, a spherical, double-contoured, 12 micron yeast that reproduces by budding
Endemic areas are Mississippi, Missouri and Ohio (USA) river valleys and southern Canada
May affect healthy patients via spore inhalation
Diagnosis: smears, cultures (Sabouraud dextrose agar at room temperature for 4 weeks generates a fluffy white colony), histology
Case reports: 53 year old African-American man with diabetes and knee mass (Archives 2005;129:e132)
Treatment: antifungal therapy
Gross: slowly enlarging verrucous plaques containing multiple small abscesses
Micro: marked pseudoepitheliomatous hyperplasia of epidermis, granulomatous and neutrophilic infiltrate, fungi are within giant cells; Blastomyces dermatitidis is a 12 micron, spherical, double-countoured yeast with broad based buds
DD: well differentiated squamous cell carcinoma
References: more information and images #1; #2
Fungi-Onchomycosis
Spread of fungi to nails
Caused by Candida albicans, Scopulariopis brevicaulis, others; often multiple fungal species
Fungi-Prototheca
Not fungi but similar features
First recognized as human pathogen in 1964; two species associated with human disease - P. wickerhamii and P. zopfii
Aerobic, achlorophyllous, algae-like, unicellular organisms in water, sewage and soil
<100 cases of human infection reported, usually via trauma or contaminated water, involving face or exposed extremities
Primary cell or spherule is called the theca; species reproduce by internal septation, forming sporangia which contain up to 20 endospores
P. wickerhamii: cells are rounder than oval/cylindrical shapes of P. zopfii
Diagnosis: corn meal agar
Treatment: amphotericin B if disseminated, surgical excision if focal cutaneous or subcutaneous
Case reports: 34 year old woman with index finger pain and swelling and hobbies of scuba diving and maintaining an aquarium (Archives 2001;125:450)
Micro: necrotizing granulomas of subcutis containing spherical organisms with central basophilia, internal septation and double layer cell walls; also multiple endospores 2-4 microns
Positive stains: GMS, PAS, mucicarmine
Fungi-Superficial fungal infections
Scalp and beard lesions may have superimposed bacterial folliculitis / perifolliculitis
May also be found on neoplastic skin lesions
Infections of stratum corneum are usually caused by dermatophytes
Spores, hyphae and neutrophils usually are present in stratum corneum or hair shafts
Associated with pseudoepitheliomatous hyperplasia
Kerion celsi: superimposed bacterial folliculitis on tinea of scalp
Majocchi’s granuloma: nodular granulomatous perifolliculitis; inflammation of dermis and subcutis by dermatophytes, usually Trichophyton rubrum
Sycosis barbae: tinera barbae with superimposed bacterial follicultis
Tinea barbae: infection of beard area of adult men
Tinea capitis: infection causing hairless patches of skin in scalp, usually in children
Tinea corporis: infection of trunk of children and adults, associated with excessive heat and humidity; scaly, red, annular plaques (“ringworm”)
Tinea cruris: "jock itch", infection of inguinal area of obese men during warm weather
Tinea pedis: "athletes foot", infection causing diffuse erythema and scaling, initially in web spaces, often with bacterial superinfection
Micro: cellulitis, abscesses, pseudoepitheliomatous hyperplasia, fungal spores and hyphae found in horny cell layer and near hair shafts; variable intercellular epidermal edema, dermal inflammation
Positive stains: PAS, GMS
Fungi-Tinea versicolor
Infection by Malassezia furfur of upper trunk
Micro: variably pigmented macules of all sizes, with orthokeratotic hyperkeratosis, yeast spores and pseudohyphae within stratum corneum; short hyphae and spores (“spaghetti and meatballs”) with GMS or PAS stains
Note: presence of fungi does not rule out coexisting inflammatory and neoplastic disorders
Fungi-Trichosporon
Case reports: 22 year old man with ALL and post-chemotherapy disseminated fungal infection (Univ Pittsburgh)
References: more information and images
Fungi-Zygomycosis
Infections caused by fungi in class Zygomycetes, including Absidia, Mucor, Rhizomucor, Rhizopus, Apophysomyces elegans (rare human pathogen)
Most zygomycosis occur in immunocompromised patients (due to leukemia, lymphoma, diabetes, transplantation), with rhinocerebral or pulmonary infection, then dissemination
A. elegans causes progressive necrosis of wound in previously healthy patients after trauma or invasive procedures
Culture: A. elegans - rapidly growing mold with sporangiophores having dark brown, funnel shaped apophyses and pyriform sporangia
Micro: extensive coagulative necrosis due to fungi with broad, sparsely septate, thin-walled hyphae; angioinvasion with thrombosis
References: Archives 1999;123:386, more information and images #1; #2
Main cause of transfusion-associated hepatitis
Associated with IV drug abuse, organ transplant, hemodialysis and health care workers
Infection is associated with cutaneous eruptions, including dermatomyositis-like photodistributed eruptions, palpable purpura, folliculitis, violaceous acral lesions, ulcers, nodules, and urticaria
Dominant patterns are vasculopathies of neutrophilic, lymphocytic, and granulomatous vasculitis and pauci-inflammatory subtypes (most common); also sterile neutrophilic folliculitis, palisading granulomatous inflammation, neutrophilic dermatoses, pyoderma gangrenosum, interface dermatitis, lobular panniculitis; single cases of dermatitis herpetiformis, benign cutaneous polyarteritis nodosa, marginal zone lymphoma, clonal plasmacellular infiltrate
Herpes simplex or varicella zoster
Painful diseases caused by herpes simplex virus or varicella zoster virus (also causes chickenpox)
After primary infection, viral particles reside in sensory ganglia and are dormant until they erupt as recurrent herpes simplex virus or shingles (zoster)
Associated with leukemia and lymphoma
Shingles has dermatomal distribution or severe involvement of trigeminal nerve-first division with corneal ulceration and herpetic keratitis
They two viruses are differentiated by culture (difficult to culture zoster) or immunologic methods
Case reports: 37 year old HIV+ man with nodules on leg
Gross: grouped vesicles on an erythematous base, later become pustules, then crusts
Micro: keratinocytes are multinucleated, acantholytic with distinct nuclear inclusions, found initially in follicular epithelium; late epidermal necrosis or full-thickness acantholysis; may have extensive dermal infiltrate, leukocytoclastic vasculitis
Due to bacterial infection around apocrine glands of axilla, occasionally perineum or vulva
Usually due to anaerobes
May produce fistulas and scarring
Treatment: excision of involved skin if medical therapy fails
Gross: abscesses, sinuses, perianal fistulas with scarring
Micro: heavy neutrophilic or mixed inflammatory infiltrate around apocrine glands with dilated lumina
Acute human immunodeficiency virus infection (HIV) is a transient illness, typically presents acute mononucleosis-like syndrome with mucocutaneous and constitutional symptoms, followed by detection of anti-HIV antibodies in peripheral blood
Associated with various conditions:
Dermatitis: interface dermatitis occurs early in HIV infection, with pronounced vacuolization of basal keratinocytes, inflammatory infiltrate is CD3+/CD8+ T cells expressing granzyme B7 and TIA1, and histiocytes; decreased Langerhans cells (Mod Path 2000;13:1232)
Drug reaction: see above
Folliculitis: infants and adults; perifollicular chronic inflammatory infiltrate, often with follicular rupture, often with marked eosinophils
Infections: scabies, fungi, mycobacteria, syphilis, bacterial angiomatosis
Maculopapular eruptions: in 25%, in trunk with possible extension to extremities; nonspecific perivascular lymphocytes and histiocytes in upper dermis, variable papulovesicular foci with necrotic keratinocytes
Papular neutrophilic xanthoma: foamy macrophages, extracellular nuclear dust, hyaline necrosis of collagen fibers
Papular pruritic eruptions: anywhere on body; may wax and wane; superficial and mid-dermal perivascular lymphocytes with eosinophils, acanthosis, parakeratosis
Psoriasis: see below
Seborrheic dermatitis: common, usually severe, involves trunk and extremities
Vasculitis: occasionally leukocytoclastic, may be due to HIV directly or CMV
Viruses: herpes simplex (20%; painful perianal or perioral ulcers with large intranuclear inclusions), severe varicella-zoster infection, CMV (ulcerative lesions at mucocutaneous junctions), molluscum contagiosum, hairy leukoplakia, anal warts, bowenoid papulosis
See also bullous impetigo
Usually affects hands and face of normal children or adults in poor health
Common, due to Staphylococcus or Streptococcus infection
Gross: erythematous macule
Micro: neutrophils beneath stratum corneum; may have subcorneal pustule
Protozoal disease in all continents except Australia and Antarctica
1-2 million new cases per year worldwide
Epidemics occur periodically in tropical regions of world; also infections in HIV+ patients
Produces crusted, indurated papule that slowly enlarges and is self limited, as well as fatal systemic illness
Disease either cutaneous, mucocutaneous or visceral
Cutaneous: usually restricted to face, scalp, arms or other exposed areas; localized, disseminated (if immune system doesn’t respond to invading parasites), recurrent (recidivans cutaneous) or post-kala azar (rare, years after visceral disease)
Mucocutaneous: usually New World disease of rural and jungle regions; occurs when primary infection with L. braziliensis becomes disseminated to upper respiratory tract, produces lesions of oral, pharyngeal or nasal mucosa with ulceration, mutilation or sometimes death
Visceral: also called kala azar; parasites throughout reticuloendothelial system, causing fever, malaise, hepatosplenomegaly, anorexia, pancytopenia, hypergammaglobulinemia; usually spares skin except for irregular areas of dark pigmentation (kala azar means “black sickness”); may cause death if untreated
Broadly divided into “old world” (tropical and subtropical Asia, India, Africa and Mediterranean) and “new world” (Americas)
Old world: usually Leishmania tropica complex
New world: L. braziliensis complex and L. mexicana complex
L. braziliensis may also produce espundia, a destructive mucocutaneous form
Human infection through bite of Phlebotomus sand fly (smaller than mosquitoes); rarely through blood contamination
Clinical presentation and prognosis vary based on species, duration of infection and immune status of patient
US infections primarily through travel and HIV infection
Diagnosis: intradermal delayed hypersensitivity test (Montenegro); culture on NNN agar; smears from ulcer; also ELISA, DNA probes, PCR
Treatment: drugs for cutaneous forms; mucocutaneous and diffuse cutaneous forms may be refractory to treatment
Micro: dermal granulomatous inflammation with prominent lymphocytes; histiocytes contain small oval organisms with bar shaped paranuclear kinetoplast
References: Archives 2002;126:471
Also called Hansen’s disease
Most US cases from immigrants
Diagnosis: PCR
Lepromatous leprosy
Micro: numerous foamy macrophages (Virchow cells, lepra) stuffed with acid-fast bacilli; granulomas in and around cutaneous nerves or infiltrating and destroying arrectores pilorum muscle; may have subcutaneous nodules (erythema nodosum leprorum)
Positive stains: acid-fast (Ziehl-Neelsen)
DD: fibrous histiocytoma
Tuberculoid leprosy
Micro: bacilli are scanty; granulomas in and around cutaneous nerves or infiltrating and destroying arrectores pilorum muscle
Multisystem disorder caused by spirochete Borrelia burgdorferi
Usually transmitted by Ixodes dammini tick mite
Causes erythema chronicum migrans (red papule with central clearing that expands slowly), acrodermatitis chronica atrophicans (disease of extremities, usually women, with erythematous, edematous, pruritic phase, followed by sclerosis and atrophy), cutaneous lymphoid hyperplasia of skin
Also affects heart, joints, nervous system
Micro: superficial and deep perivascular infiltrate of lymphocytes, plasma cells and eosinophils
Positive stains: Warthin-Starry (for spirochetes)
Rare; may occur in HIV+ patients
Micro: histiocytes have Michaelis-Gutmann bodies, rarely contain gram negative organisms
Caused by human molluscum contagiosum poxvirus
Multiple nodules on skin, trunk, anogenital region, due to skin to skin contact; also sexually transmitted
Gross: multiple firm, pruritic, pink-tan nodules, up to 4 mm, with central cores containing white keratinous material
Micro: characteristic findings of sharply delimited dermal lesion containing proliferating epithelium; molluscum bodies present (large cells with cytoplasmic, faintly granular eosinophilic inclusions that displace nuclei; contain viral particles); may have intense dermal inflammatory infiltrate; rarely metaplastic ossification
DD: keratoacanthoma
May cause ulcerations, abscesses, rheumatoid-like nodules, histiocytic reactions, panniculitis
Most commonly due to M. kansasii, M. marinum, M. ulcerans
Case reports: 52 year old woman with foot infection (Univ Pittsburgh)
Characteristic skin manifestations are petechial eruption in a glove and stocking distribution, reticular truncal erythema, and "slapped cheek" sign
Clinically manifests as Fifth’s disease; atypical presentations resemble asymptomatic papular eruption, Sweet’s syndrome, myopathic dermatomyosis, lupus, lower extremity palpable purpura
May be due to delayed type hypersensitivity, antibody dependent cellular immunity against microbial antigens in epidermis or endothelium, or circulating immune complexes
Micro: interstitial histiocytic infiltrate with piecemeal fragmentation of collagen and mononuclear cell-predominant vascular injury pattern; also interface dermatitis, eczematous alterations, papillary dermal edema; occasionally mesenchymal mucinosis, leukocytoclastic vasculitis
References: Hum Path 2000;31:488
Chigger-borne zoonosis of tropical Asia and western Pacific islands
Infected large number of soldiers in World War II
Today, a frequent cause of febrile illness leading to hospital admissions in indigenous populations
Caused by Orientia (formerly Rickettsia) tsutsugamushi, maintained in nature by trombiculid mites, transmitted to humans by larval mite (chigger) during feeding
Distinguished from Rickettsiaceae family by differences in cell wall
Micro: detected in endothelial cells of skin biopsies, and other organs sampled
References: Mod Path 2001;14:752
Diffuse, pruritic, erythematous macules and papules may occur 2 days to 7 weeks after routine smallpox vaccination (usually 7-11 days)
Serious but uncommon complications include eczema vaccinatum, vaccinia necrosum, generalized vaccinia
Less serious but more common include keloid, contact dermatitis, erythema multiforme, pityriasis rosea, granuloma annulare
Treatment: symptomatic
References: Archives 2004;128:1173, smallpox and mimics
Secondary lesions are maculopapular, and resemble drug eruption, lichen planus, psoriasis
May present as moth-eaten alopecia on scalp, mucous patches on tongue
Occur on face and trunk
Diagnosis: serology
Gross: scaly, flesh-colored to erythematous papules or annular plaques; copper macules on palms and soles
Micro: dense perivascular or diffuse plasma cell infiltrate with marked endothelial swelling and proliferation in blood vessels is characteristic; may have noncaseating granulomas, vacuolar interface change, acanthosis, spongiosis, lymphocyte exocytosis
Positive stains: Steiner stain (71% sensitive)
Cutaneous disease uncommon in US
Lupus vulgaris
Reactivation form of tuberculosis
Chronic cases are associated with squamous cell carcinoma
Diagnosis: culture or PCR
Gross: facial lesions with small, firm nodules in underlying, irregular red patch with elevated borders; nodules become pale and tan when pressed with a glass slide; variable ulceration
Micro: sarcoid-like or necrotic granulomas in dermis; rare acid-fast bacilli
Papulonecrotic tuberculid
Associated with tuberculosis, but usually no organisms present
Micro: dermal necrosis, poorly formed granulomas, vasculitis, edema
Erythema induratum of Bazin
Also called nodular vasculitis if no coexisting tuberculosis
Rare, more common in past
Presents as recurrent tender subcutaneous nodules on calves of women with tuberculin hypersensitivity
Micro: granulomatous vasculitis affecting subcutaneous large vessels (may need multiple serial sections to identify); also granulomatous inflammation of lobules of subcutis; lesions may contain acid-fast bacilli by PCR
Caused by bacterium Francisella tularensis found in animals (especially rodents, rabbits, and hares), transmitted by ticks, deer flies
Symptoms: sudden fever, chills, headaches, diarrhea, muscle aches, joint pain, dry cough, progressive weakness
Also pneumonia, skin/mouth ulcers, lymphadenopathy, eye involvement
References: outbreak in Kosovo
Virus associated trichodysplasia spinulosa
Very rare; <10 cases reported
Cutaneous eruption of spiny papules due to polyoma virus infection
Usually affects face and ear, less often trunk and extremities, may cause alopecia
Associated with kidney transplant, acute lymphocytic leukemia
Similar to cyclosporine-induced follicular dystrophy and pilomatrix dysplasia
Micro: abnormally maturing anagen hair follicles (no papillae, ectatic infundibula) with excessive inner root sheath differentiation, and hyperkeratotic infundibula
EM: intranuclear polyoma-type virus particles
DD: keratosis pilaris (usually arms and legs, small ecstatic infundibula with keratin plugs), lichen spinulosis (children and adolescents, extensor arms, lateral thighs, neck and buttock, minute filiform horny spines grossly due to follicular infundibular hyperkeratosis), drug induced folliculitis
References: AJSP 2005;29:241
Also called verrucae
Cutaneous and mucosal lesions caused by various types of human papillomaviruses (HPV), a type of papova virus
Usually resolve in 6-24 months
Micro: focal epidermal hyperplasia with hyperkeratosis and parakeratosis, papillomatosis (not verruca plana), may have trichilemmal keratinization; koilocytes (keratinocytes in upper squamous layer with vacuoles, large cytoplasmic eosinophilic aggregates, pyknotic nuclei); tangential sections may show squamous cells surrounded by inflamed stroma; older lesions may lack cytoplasmic changes; viral nuclear inclusions are basophilic
Positive stains: HPV by in situ hybridization
EM: eosinophilic aggregates are tonofilaments
DD: squamous cell carcinoma (may resemble tangential cuts of condyloma accuminatum)
Condyloma accuminatum
Also called venereal wart
Usually due to HPV6
Perianal, vulva, glans penis, mucosal membranes of oral cavity
Gross: soft, tan, cauliflower-like masses
See also Vulva, Penis, Cervix, Anus chapters
Epidermodysplasia verruciformis
Autosomal recessive disorder of multiple flat warts on face or distal extremities, often disseminated throughout the body
Usually HPV 5 or 8, less commonly 3, 4, 51
Rarely X linked recessive or autosomal dominant transmission
Often appear before age 10 years or after renal transplantation
30-50% progress to invasive squamous cell carcinoma, mean age 31 years
Equivocal cases are best distinguished by histology and viral testing, in context of clinical setting
Treatment: excision or locally destructive methods
Gross: flat, skin-colored, red or hyperpigmented papules resembling flat warts or scaly brown pityriasis versicolor-like macules and patches; also seborrheic keratosis-like
Micro: classic features are mild to moderate acanthosis and hyperkeratosis; large cells with blue-gray cytoplasm, perinuclear halos, often dysplastic changes; more commonly has irregular granular layer with rare perinuclear halos
Positive stains: HPV
References: AJSP 2000;24:1400
Verruca plana
Usually due to HPV10
Flat, occurs in crops/clusters on face and hands
Micro: involuting lesions may have chronic inflammatory infiltrates in dermis and epidermis with degenerative epithelial changes
Verruca plantaris
On soles of feet; painful; covered by callus
Micro: invaginated with numerous coarse, basophilic, intracytoplasmic keratohyalin granules resembling molluscum bodies
Verruca vulgaris
Usually due to HPV2
Occur on hands as elevated, hard, rough, flesh-colored lesion
If surface is peeled, undersurface is pink and granular
Gross: exophytic papules, either single lesions or linear; appear serrated
Micro: striking papillomatosis (upward displacement of dermal papillae), stratum corneum exhibits parakeratosis with pointed mounds resembling church spires, extravasated erythrocytes or hemosiderin; granular layer is thickened with prominent keratohyalin granules and keratinocytes displaying perinuclear clearing (koilocytosis, lost in older lesions); lymphocytic infiltrate in upper dermis
Infestations
Skin lesions due to direct irritant effects, immediate or delayed hypersensitivity or specific effects of venom
Bites: urticaria, inflammed papules or nodules, variable ulceration
Causes hyperpigmentation and scratch marks (excoriations)
Dermatobia hominis flies are acquired during travel to endemic area
Female botfly attaches eggs to abdomen of biting arthropod, eggs hatch, and first stage larvae burrow into skin through insect bite, hair follicle or other wound; larvae spend 4-14 weeks in skin developing into third stage larva or “instar”, up to 2 cm; larvae then emerge
Treatment: petroleum jelly over skin opening to cause larvae to migrate to surface
Case reports: 61 year old woman who traveled to Belize for jungle hiking and ocean snorkeling with pruritic lesions on back, thigh and supraclavicular area (Archives 2001;125:453)
Gross: resemble insect bites, allergic reactions, herpes virus, molluscum contagiosum, bites of mite Sarcoptes scabiei; enlarging lesions may resemble cellulite, pyogenic furuncle or infected sebaceous cyst
Bite causes extensive necrosis
Mites are commonly present in inflamed follicles, but are usually nonpathogenic
Common in dogs
Causes pruritis, enlarged local lymph nodes
Eggs are attached to hair shaft (nits)
References: more information
A sexually transmitted disease
Produces burrows and extremely pruritic erythematous papules on interdigital skin, palms, wrists
Micro: burrow appears as cleft in upper epidermis containing mite body parts; epidermis exhibitis acanthosis, parakeratosis, spongiosis, with dense eosinophilic dermal infiltrate
Sand flea that burrows into human skin and skin of mammals, causing the disease tungiasis
Parasite common in tropical locations (South America, Caribbean, Africa, Pakistan, west coast of India)
Single flea causes local discomfort; multiple bites cause debilitation and secondary infections (tetanus, gas gangrene)
Gross: nodular lesion
Micro: skin biopsies have exoskeleton, hypodermal layer, trachea, digestive tract and developing eggs; striated muscle in 47%, posterior end in 43%; head usually absent
References: Archives 2002;126:714
Granulomatous but non-infectious disorders
Small clusters of erythematous papules or large, deep, indurated, violaceous nodules resembling lymphoma
Micro: inflammatory and granulomatous reactions with dense superficial and deep lymphocytes, eosinophils and plasma cells; variable parakeratosis, spongiosis, acanthosis, epidermal erosion; may have lymphoid germinal centers resembling lymphoma, with destruction of adnexae and atypia
Positive stains: CD30 (focal, may involve atypical cells, AJSP 2003;27:912)
Due to talc, silicon, lipid, zirconium, beryllium, prior surgery or arthropod bites, tattoos, keratin or urates; all may cause granulomatous reactions
Micro: polarizing microscope demonstrates talc, silica, lipids; beryllium is associated with necrotizing and granulomatous reaction
Interstitial granulomatous dermatitis with arthritis
Uncommon; first described in 1993
Linear inflammatory indurations on lateral aspects of trunk (“rope sign”), also plaques or papules, associated with systemic connective tissue disease; usually in women
Arthritis is usually symmetric, and involves fingers, wrists, elbows and shoulders; associated with positive rheumatoid factor, autoantibodies and elevated erythrocyte sedimentation rate
Case report: disease without rope sign (Hum Path 2004;35:892)
Micro: diffuse dense inflammatory infiltrate of histiocytes within reticular dermis, focal degenerated collagen and elastic fibers, palisading histiocytes; variable neutrophils, eosinophils, lymphocytes, mucin and vasculitis
DD: granulomatous drug reactions (vacuolar interface changes and often epidermotrophism of lymphocytes, resolve with discontinuance of drug), rheumatoid dermatosis, interstitial granuloma annulare, necrotizing granuloma
References: Hum Path 2004;35:779 (editorial)
Interstitial granulomatous drug reaction (dermatitis)
Due to beta blockers, calcium channel blockers, lipid lowering agents, ACE inhibitors, diuretics, NSAIDs, antihistamines, antidepressants, oral hypoglycemic agents; often more than one of above
Mean duration of 5 years before onset of eruptions; resolve an average 8 weeks (range 1-40) after drug is stopped
May be due to exaggerated immune response to drugs
Case report: 74 year old woman with violaceous/erythematous nonpruritic plaques for 18 months (Archives 2004;128:e129), delayed cutaneous hypersensitivity reaction to hirudin (Archives 2001;125:1585)
Gross: violaceous to erythematous, nonpruritic plaques with bizarre shapes or annular morphology on skin folds (axilla, inner arms, groin, medial thighs, popliteal fossa)
Micro: diffuse granulomatous dermatitis with interstitial histiocytes and giant cells near collagen and elastic fibers, often with piecemeal fragmentation of collagen, giant cell engulfment of elastic fibers and variable interstitial mucin; rare collagen necrobiosis; usually interface dermatitis with basilar vacuolopathy, focal dyskeratosis with lymphocytes at dermoepidermal junction; usually tissue eosinophilia, lymphoid atypia with hyperchromatic nuclei, convoluted nuclear contours (including a few cerebriform nuclei in dermis), variable involvement of hair follicles and acrosyringia; usually no fibrin deposition within vessels or vasculitis
DD (clinical): cutaneous T cell lymphoma (cerebriform nuclei in epidermis), erythema annulare centrifugum, granuloma annulare (vasculitis or vasculopathy present), subacute cutaneous SLE
Affects skin, lymph nodes, organs
Diagnosis of exclusion
Patients often have anergy to delayed hypersensitivity tests
Gross: variable cutaneous features – single/multiple, macules to large plaques or nodules; may have central clearing
Micro: dermal nests and clusters of noncaseating epithelioid granulomas with minimal inflammatory cells and variable giant cells
DD: tuberculosis, atypical mycobacteria, syphilis, fungi, reaction to metals (zirconium, beryllium) or lymphoma, foreign body reaction
Blistering disorders
Key features are level of plane of separation, presence or absence of acantholysis and immunofluorescent pattern
Large intraepidermal bullae witho