Dermatology

Type I hypersensitivity Type II hypersensitivity Type III hypersensitivity Type IV hypersensitivity

Ag induces cross-linked of IgE Ab directed against cell-surface Ag-Ab complexes deposited @ Memory Th1 cells, release
bound to mast cells, with Ags, mediates cell destruction various sites, induces mast cell cytokines that recruit and 
release of vasoactive via ADCC or Complement degranulation via FcR, PMN macrophages
mediatory (pre-formed) degranulation, damages tissue  Allergic contact dermatitis
 Urticaria ● Pemphigus  Vasculitis  Chronic atopic dermatitis
 Acute atopic dermatitis  PSR
Normal Skin Histology
Come Get Sun Burned!
- Layers
o Epidermis→ Stratum Corneum, Granulosum, Spinosum & Basal layer (~30 days for the basal layer to become the Corneum)
o Dermis
- Adhesion
o Desmosome: holds cells together in the strata corneum, granulosum, and spinosum
o Hemidesmosome: holds cells together in stratum basale and basement membrane

Basic Morphology
Macule - Flat, non-palpable lesions; indicates a lesion w/ color  without elevation above skin surface
- Usually < 1 cm (and a “patch” is sometimes used to indicate a flat, non-palpable lesion > 1 cm)
Papule Superficial, circumscribed, palpable lesion elevated above skin surface; diam < 1 cm
Plaque Palpable lesion elevated above skin surface; diam > 1 cm
Nodule Firm (indurated) lesion that is thicker or deeper than average papule or plaque (usually ~ 1cm)
Dermal component that isn‟t palpable (e.g., cyst)
Vesicle Elevated lesion that contains clear fluid; small blister < 1 cm diam
Bulla Elevated lesion that contains clear fluid; large blister > 1 cm diam
(Bullae is plural)
Pustule Superficial elevated lesion that contains yellow fluid (pus) w/in or beneath epidermis, generally protein-rich and
containing neutrophils
Arrangement Can be  annular, linear, dermatomal, herpetiform, grouped
Purpura - Extravasated blood that does NOT blanch upon diascopy (pushing a glass slide against the skin)
- If blood in contained w/in vascular system, then it would blanch w/ diascopy
- Note: if palpable purpura, then it is vasculitis until proven otherwise
Erosion Partial loss of epidermis
Ulcer Focal loss of epidermis
Acantholysis Loss of attachment b/t epithelial cells resulting in separation & rounded appearance of these cells (from recoil)
 Seen in Pemphis Vulgaris
Acanthosis  thickness of spinous layer of epidermis, as result of  in # or size (or both!) of epidermal cells (epidermal
hyperplasia)
 Seen in Psoriasis
Ballooning Marked swelling of spinous cells d/t intracellular edema
degeneration  Seen in Herpes
Granuloma Collection of histiocytes – with or without epithelioid cells & multinucleated giant cells
Tuberculoid granulomas = granulomas surrounded by lymphocytes
Sarcoidal, “naked” granulomas = granulomas without dense inflammatory lymphocytes surrounding them
Hypergranulosis  thickness of granular cell layer, as result of  # of keratinocytes containing keratohyaline granules
Hyperkeratosis  thickeness of horny cell layer – w/ or w/o  thickness in granular cell layer
3 types  basket-weave, laminated, and compact
Leukocytoclasis Fragmentation of leukocytes, resulting in nuclear “dust”
 Seen in LCV (Leukocytoclastic vasculitis)
Lichenification Accentuation of skin markings (clinical term) – may be a response to scratching
Parakeratosis Retention of nuclei in horny layer, assoc/ with  or absence of granular cell layer
 Seen in Psoriasis
Psoriasiform Epidermral hyperplasia resembling Psoriasis, characterized by  regular elongation of rete ridges to about equal
hyperplasia lengths and  elongation of dermal papillae
Scale crust Collections of inflamm cells, serum, and/or fibrin and keratotic material, usually covering erosion or ulcer
 Seen in Acute Spongiotic Dermatitis
Spongiosis Intercellular edema b/t squamousa cells of epidermis & adnexal epithelium, resulting in widened intercellular
spaces. Marked spongiosis may lead to vesicle formation
 Seen in Acute Spongiotic Dermatitis
 5 inflammatory reactions
Contact Dermatitis 1. Papulosquamous: conditions that are red and scaly
has 2 types  True (20%) and  Irritant (80%) 2. Eczematous: 3 stages   acute,  subacute,  chronic
3. Vascular: diffuse red eruptions like hives & drug-induced skin reactions
Allergic Contact Dermatitis 4. Dermal: conditions w/ deep component in skin, little or no epidermal 
- Is “true” dermatitis 5. Vesicobulbous: associated w/ blisters
- Common causes  nickel and poison ivy (hapten1 of poison ivy is Urushiol)
- Pathophysiology
o Specialized form of delayed, Type IV hypersensitivity  contrast w/ Atopic Dermatitis
- Histology
o Acute: spongiosis, vesiculation, eosinophils
o Chornic: psoriasiform epidermal hyperplasia
- Gross Appearance  often linear or geometric, and well-demarcated
o Usually localized to site of contact (helpful for hx)
- Course of Disease/ Clinical stages
o Acute: inflammatory mediators cause spongiosis (histological)  vesicles & blisters (clinical manifest)
o Subacute: vesicles rupture  erosions, scales (dried blister roof), and crust (dried serum/ blood)
o Chronic: scratching & rubbing result in epidermal hyperplasia (histologically)  thickening and lichenification (clinical manifest),
become psoriatic
- Gold standard for Dx  patch testing (using a standard panel of 24 things; evaluation @ 48, 72 hours to see if it‟s delayed-type hypersensitivity)
- Differential Dx  “itch-scratch,” irritant contact, atopic dermatitis, stasis dermatitis, seborrheic dermatitis, erythematous form of acne rosacea

Atopic Dermatitis
- Pathophysiology  Allergic Dermatitis is Type IV hypersens
- Clinical Stages
o Acute  Type I hypersensitivity
o Subacute
o Chronic  Type IV hypersensitivity
- Eval of PT  hx & PE usually sufficient, but also… biopsy to confirm dermatitis; also can do patch test
- Treatment  remove causative agent (#1), topical steroids (if severe), anti-histamines (that  H1 receptors)

LCV (Leukocytoclastic Cutaneous Vasculitis), a small vessel vasculitis… i.e., Hypersensitivity Vasculitis
- DEF: Diverse group of disorders: segmental inflammation + necrosis of blood vessels
- Etiology  may be 1, d/t a systemic disorder, or idiopathic
- Pathophysiology  Type III hypersensitivity, with circulating immune complexes depositing in small blood vessels,  complement, and attract
neutrophils  degranulation of neutrophils and monocytes  release of lysosomal enzymes and toxic O2 metabolites  tissue damage &
vascular injury
o Involves only small vessels, esp post-capillary venules!
- Appearance
o Palpable pupura ( doesn‟t blanch on diascopy), edematous urticaria-like lesions, hemorrhagic macules or vesicles
o Lesions usually occur @ lower extremities, dependent areas, or pressure points
o Extra-cutaneous involvement occurs but is uncommon… GI, genitor-urinary, or neurological sx should raise suspicion about systemic
vasculitis being the Dx
o Typically presents 7-10 days after exposure to inciting agent
- Biopsy would should  lymphocytic infiltrate of blood vessels
- Treatment
o Treat underlying cause (esp if d/t meds, infections)
o H1 blockers (antihistamines) to alleviate sx of palpable purpura
o H1 blockers + NSAIDs
o Colchinine can be added or substituted for above agents; if not effective, then trx with Dapsone
o IFN clears lesions in Hep C
o Steroids: rarely indicated!

1
Hapten = small molecule that can elicit an immune response only when attached to a large carrier (e.g., a protein)
 Urticaria
- Epidemiology
o Lifetime occurrence: 1-5%
o Women > men, except in delayed-pressure urticaria
- Subtypes
o Acute (if < 6 weeks): idiopathic (50%), URTI (40%), drugs (9%), food (1%)
o Chronic (if > 6 weeks): 50% free in 1 year; 65% free in 3 yrs; 85% free in 5 yrs
- Pathophysiology
o Type I hypersensitivity  Ag induces cross-linked of IgE bound to mast cells, with release of vasoactive mediatory (pre-formed)
 Note that some ppl can have autoimmune urticaria (anti-FcR, anti-IgE antibodies)
o Secretory granule preformed mediators  histamine, proteoglycans, tryptase & chymas, carboxypeptidase A
- Histology
o Sparse superficial peri-vascular & interstitial inflammatory infiltrate
o Mixed-cell infiltrate including activated T-cells, monocytes, eosinophils, & mast cells
- Clinical Features
o History of allergy
o Wheal: white or red evanescent plaques, d/t local edema… usually lasts 12-24 hrs
o Flare: a “red halo” that surrounds the wheal
o Pruritic or stinging
- Systemic associations, which may indicate anaphylaxis  palpitations, nausea, malaise, dizziness, syncope, wheezing, vomiting, diarrhea, fever,
chills, abdominal pain, arthralgia, myalgia, headache
- Diagnosis  skin biopsy is not routine and is only indicated if lesions last > 24 hrs
- Treatment
o Cromoglycate (mast cell stabilization), Cromolyn sodium
o Anti-histaminergics (mainstay) + LK antagonists (Monteleukast)
 They work synergistically
o Doxepin (a TCA with anti-H1 receptor properties and activity against PAF)
o Corticosteroids  AA pathway mediators & cytokines, but have NO effect on histamine
o Immunosuppressants (e.g., Cyclosporine and FK506)  cytokine production
o Avoid mast-cell degranulating agents  e.g., EtOH, anti-cholinergic preparations, ASA, NSAIDs, narcotics, Polymxyin B

Erythema Multiforme
- Acute, self-limited skin disease
- Pathophysiology
o Skin-directed immune reaction in predisposed individual in the setting of an infection or less commonly, other insult  HSV is most
commonly associated infection (HSV-1 and HSV-2)
 Also: bacterial infection by Mycoplasma pneumonia
 Fungal infections
 Drugs < 10%
 Exposures (e.g., poison ivy)
 Systemic disease (rare)  inflamm bowel disease, SLE, Behcet‟s Disease
o Evidence for replicating HSV in lesions
 HSV proteins found in affected epidermis
 HSV DNA in early red papules or outer zone of target lesions in 80% of PTs
 Virally-encoded antigens on keratinocytes
o EM lesion thru part of HSV-response
 HSV DNA recruits IFN-producing Th1 cells
 Immune response to auto-antigens released by lysed/ apoptotic viral antigen-containing cells
- Findings
o Keratinocyte necrosis; spongiosis; superficial dermal edema
o Small vessel vasculitis: extravasated RBCs, perivascular inflammation
- Clinical Presentation
o “Target” or “iris” lesion (fairly distinctive  usually a clinical dx)
 Present within 24 hrs
 Pruritus or burning may accompany the lesions (“skin pain” might be CC of PT)
o Mild cases: EM minor (involving skin + 1 mucosal surface (e.g., vaginal mucosa))
 Lesions are non-blanching
o More severe cases: EM major or Stevens-Johnson Syndrome (skin + more than 1 mucosal surface)
 Most extensive & aggressive form of SJS: Toxic Epidermal Necrolysis (TEN)
 TEN is 1 in a million of the normal pop, but 1 in 1000 in those w/ HIV
o No sequelae, except ocular sequelae in EM major without adequate eye care
o Recurrent is common in HSV-related EM
- Course of Disease
o Of those w/ SJS & TEN: 20-30% mortality
- Treatment
o Topicals
 Antiseptics for eroded skin
 Antiseptics/antihistamine/local anesthetics for mucosal lesions
 Ophthalmic preparations for eye care (consult ophthalmology)
o Systemic
 Treat identifiable precipitators when possible though often only symptomatic treatment needed
 Oral antihistamines may reduce stinging and burning
 In severe EM, early oral corticosteroids considered
o Prophylaxis
 Acyclovir shown effective in double-blind, placebo controlled study, though valacyclovir and famcyclovir also employed
 Occasionally benefit extends even after discontinuation of antiviral

Urticaria Erythema Multiforme

Central zone is normal skin (white or yellow) Central damaged skin (dusky color, bullous, crusted)
Lesions are transient (usually < 24 hrs) Lesions are fixed (usually > 7 days)
New lesions daily All lesions appear w/in 72 hrs
Associated w/ swelling & angioedema No swelling edema

Clinical approach to Blistering Eruptions

- Hx & PE
- Do biopsy to see histology
- Direct immunofluorescence (DIF): detects Ab that is deposited in skin
- Indirect immunofluorescence: detects circulating Ab
- Salt-split skin used to differentiate autoimmune diseases w/ similar DIF
o E.g., DIF can be localized to epidermal side of the split (rete ridges); “blister roof”
o E.g., in EBA (Epidermolysis bullosa acquisita), DIF localized to blister floor (dermal papillae)

How Blisters Form

- Autoimmune  Ab against structural or adhesive molecules
- Inherited  genetics defects in structural or adhesive molecules
- Infectious  exfoliative toxins (e.g., Staph aureus)
- Other  spongiosis, ballooning degeneration, physical (friction, thermal injury, etc)
Intra-epidermal Blistering
1. Autoimmune: pathogenic autoantibodies
– Pemphigus foliaceus: Dsg1
– Pemphigus vulgaris: Dsg3
2. Infectious: S. aureus
– Phage group II, type 71 (Exfoliative toxins A &B)
– Toxin targets Dsg1
– Staph Scalded Skin Syndrome
– Bullous impetigo
3. Genetic/Other
Bullous Phemigoid
- Most common autoimmune subepidermal blistering disease (elderly)
- May be drug-induced (Furosemide, Penicillamine, antibiotics, potassium iodide, gold, Captopril)
- Assoc w/ tissue-bound & circulating Abs directed against BPAg2 (i.e., Collagen XVII) and BPAg1
- Presentation
o Intensely pruritic eruption w/ widespread blister formation; mucosal involvement is uncommon
o In early stages, urticarial lesions are present
- Course of Disease
o Chronic disease characterized by spontaneous exacerbations & remissions
- Cicatrical Pemphigoid is variant w/ mucosal involvement
Pemphigus Vulgaris
- Pemphigus is a group of autoimmune blistering diseases of skin & mucous membranes
- Etiology  can be drug-induced (Penicillamine, Captopril) and Paraneoplastic variants exists (like non-Hodgkin‟s lymphoma)
- Problem  IgG autoantibodies target desmosomes, which play a major role in cell-cell adhesion of keratinocytes. The component of
desmosome (specifically the Desomglein) against which the antibodies are formed depends on the Pemphigus variant
o In Pemphigus Foliaceus, antibodies are directed against Desmoglein-3
 This is more superficial
o In Pemphigus Vulgaris, antibodies are directed against Desmoglein-1
- Presentation
o Flaccic blisters and mucocutaneous erosions
- Findings
o H& E  intra-epidermal blister w/ suprabasilar acantholysis… desmosome disruption; cells recoil and tend to round out
o DIF  intercellular IgG & C3
- Treatment
o Now: mainstay is systemic corticosteroids
o Immunosuppressive agents are often used for their corticosteroid-sparing effect
o IVIg is blood product prepared from pooled plasma that has immunomodulatory effects when used in high dose (mechanism not
entirely known)
o Rutuximab: anti-CD20 monoclonal Ab that targets B cells. Very effective for PTs who are refractory to standard
immunosuppressive therapy
 If you knock out Dsg-1 (as in P. Foliaceus), you will get superficial skin blisters, since you still have Dsg-3, which holds
together the base
 But if you knock out Dsg-3, Dsg-1 is not sufficient to keep all the layers together, and you will get suprabasilar blisters

Pemphigus Pemphigus
Foliaceus Vulgaris
Antigen Dsg-1 Dsg-3

Blister Location Subcorneal Suprabasilar

Skin Lesions + 50%

Mucosal Lesions  > 90%

Prognosis Survive Die w/o treatment

Sarcoidosis
- Systemic granulomatous disorder of unknown origin, that most commonly involves the lungs which may involve essentially any organ system
- Epidemiology
o Occurs in PTs of all races, ages, and both sexes
 In US,  incidence in African Americans
 Worldwide, highest incidence in Sweden
o Bimodal age distribution: (25 and 35) and (45-65)
o Greater # of PTs with new-onset Sarcoidosis are reported in winter & spring
- Genetic susceptibility: HLA-1, HLA-B8, and HLA-DR3(and HLA-DR3is associated with good prognosis) are associated w/ Sarcoidosis
- Pathophysiology  see below
- Clinical Presentation
o Cutaneous manifestations of Sarcoidosis are seen in up to 1/3 of PTs – may be 1st clinical sign of disease
o Can be flesh-colored, or red-brown to violaceous papules & plaques most often on face, lips, neck, upper back, and upper extremities
o Erythema nodosum is a non-specific inflammatory skin finding –typically on shins – associated w/ acute, transient Sarcoidosis
o Lymphophenia (exact reason unknown!)
- Presentation can vary
o Erythematous plaques
o Hypertrophic scars
o Apple jelly color on diascopy
o Could be tinea corpis
o Could be tuberculoid sclerosis
- Investigations
o Diascopy would show “apple jelly” color (no blanching)
o ACE level  in 60% of PTs
 Monitor ACE levels to monitor response to therapy
o  Ca2+ levels b/c of  calcitriol synthesis by sarcoidal histiocytes

- Treatment (depends on severity and progression) & Prognosis  goal is to interrupt antigen processing,  cytokines (like TNF, IL-1, IFN), 
chemotaxis
o Corticosteroids are mainstay (topical, intralesional, or systemic)
o Hydroxychloroquine and Chloroquine (antimalarials) are used to control skin manifestations
o Other Trx  immunosuppressant drugs like Tacrolimus, TNF inhibitors (Infliximab), surgical excision
o About 60% spontaneously resolve and 10-20% spontaneously resolve w/ steroid use
o > 80% with EN and acute Sarcoid have spontaneous resolution
 Acute, transient Sarcoidosis is a good prognostic factor
o Chronic & progressive in 10-20%; fatal in 1-5%

Pathophysiology of granulomas in general (not just of Sarcoidosis)

- Etiology  Antigenic trigger is unknown; can be autoimmune or infectious; can be d/t mycobacteria, HHV8; can
be environmental as well (seasonal)
- Antigen presentation CD4+ cells (Th1 subtype) initiates formation of epithelioid granulomas (converted
from macrophages) that surround a central focus
- Immunosuppressans as treatment don‟t create fulminant disease and  infection is unlikely
Erythema Nodosum
- Results from immunologic rxn triggered by drugs, systemic illness, bacterial, viral, and fungal infections
o Bugs  Strep
o Drugs  estrogens, OCs
o Systemic infections  Inflammatory Bowel Disease (UC & Crohn‟s)
o Other etiologies are likely d/t hormones
- Pathophysiology
o Hypersensitivity rxn to variety of antigenic stimuli; result of complex deposition in and around venules of CT septa of subcutaneous
fat  septal panniculitis w/ widened septae
o  neutrophils early in lesions  production of reactive oxygen intermediates  ROIs may cause inflammation & tissue damage 
lymphohistiocytic infiltrate w/ multinucleated giant cells
o No vasculitis or necrosis
- Presentation
o Tender/ painful erythematous subcutaneous nodules
o Usually distributed symmetrically over pre-tibial; sometimes elsewhere (like upper extremities)
o In later stages, lesions have bruise-like appearance
o (May be accompanied by fever, arthralgia, and malaise)
- Investigations
o Generally not required for Dx
o Review of associated meds
o ALSO, PPD, CXR, GI eval
o Biospy if still uncertain
- Treatment
o Aimed at underlying medical conditions
o Spontaneous resolution usually w/in 3-6 weeks
o NSAIDs (e.g., Indomethacin, Naproxen)
o Systemic steroids effective in severe cases if infection isn‟t etiology
o KI (potassium iodide)  enhances lysis & digestion of necrotic tissue,  neutrophils chemotaxis & suppress neutrophils-generated
oxygen intermediates
Acne Vulgaris
- DEF: multifactorial disease of pilosebaceous unit
- Genetic predisposition: #, size, activity of sebaceous glands
- Pathophysiology
o “Pilosebaceous Unit” = sebaceous gland + associated hair follicle
 SG glands are high in #: face, scalp, central chest, back
o SG produces sebum via holocrine secretion  sebum in glands & ducts is sterile and contains TAGs, wax, & sterol esters, squalene,
& FFA
o Sebaceous follicles are rich in microorganisms including Malassezia spp (yeast living on skin), Staph epidermidis, and
Propionibacterium acne (gram + rod)
 Lipases from P. acne split TAGs  FFA
 FFAs are comedogenic and alter keratinization w/in infundibulum   cohesiveness of corneocyts  obstruction
of follicle ( entrapment of bacteria)
 FFAs are chemotactic and attract neutrophils
 Skin response to P. acne, thru TLR-2 pathway: release of IL-1, IL-8, and TNF
o Note that DHT (dihydrotestosterone – which is 5x more potent than testosterone) induces growth of sebaceous gland and  sebum
production
- Clinical characteristics
o Comedones (lesions), papules, pustules, cysts, scarring
o Non-Inflammatory
 Closed comedones: 1 mm skin-colored papules; no apparently follicular opening or erythema
 Open comedones: dome-shaped papules w/ dilated follicular outlet
 Blackheads: ruptured lesion and oxidized keratinized material
 Whiteheads
o Inflammatory: papules, pustules, nodules, cysts
o Note: Acne Vulgaris may cause significant psychological & social impact
- Dx→ May culture to dx folliculitis
- Investigatiosn  do endocrine work-up if necessary
o PCOD (polycystic ovarian disease): presents as acne, obesity, hirsuitism, amenorrhea, and glc intolerance
o CAH (congenital adrenal hyperplasia): assoc w/ acne
o  DHEAS in adrenal androgen-secreting tumor
o Notes: Eunuchs don’t get acne b/c of lack of testicular function
- Treatment
o Retinoids (topical/systemic):  sebum prod. by  sebaceous gland size, normalizes follicular keratinization, & indirectly  P. acne
o Topical or systemic antibiotics   to suppress P. acne growth,  intrinsic anti-inflamm properties
o Spironolactone: androgen receptor blocker & inhibitor of 5-reductase
o YAZ (2nd –line trx for female PTs)
o Other: chemical peels, surgery, intralesional steroids
Psoriasis
- Polygenic disease w/ various triggering factors
o Medications  Lithium, -blockers, anti-malarials, rapid corticosteroid tapers (causes “erythroderma,” in which the person is red from
head to toe, d/t vasodilation)
o Trauma (Koebner Phenomenon: skin lesions appearing on lines of trauma; may result from either a linear exposure or irritation)
o Infections
o Hypocalcemia, stress
o Other: alcohol, smoking
- Epidemiology  up to 2% of US pop
o Usually 3rd decade of life; bimodal incidence (peaks @ age 29 and 55)
- Genetics  35-90% have Fam Hx +
o HLA association  HLA-Cw6 (most definitive; has  risk 9-15x), HLA-B27
- Pathogenesis  we think it‟s immunologic b/c immunosuppressive drugs exhibit efficacy in treatment!
o Predominantly Th1 response:  IL-2, IFN, TNF
 TNF recruits keratinocytes, which synthesize angiogenic cytokines (e.g., VEGF)
o No Th2 response (antibodies are NOT involved)
o APCs induce other cytokines too
o Epidermal hyperproliferation
o Abnormal terminal differentiation
o Dysregulated inflammation w/ multiple potential triggers
o Stimuli are drugs, infections, stress
o [ involvement of  CD8  CD4,  dendritic cells ]
o 3 major events   initial  T cells,  migration of T cells into skin (T effector),  impact of cytokine release by T cells & other
(APCs)
- Histology
o Acanthosis w/ elongated rete ridges
o Hypogranulosis
o Parakeratosis
o Dilated blood vessels & perivascular infiltrate of lymphocytes & neutrophils
o Munro’s Abscess: collection of neutrophils in epidermis
- Presentation
o ~80% have nail changes
 Pitting of nails
 Auspitz sign (see below)
o Scaly erythematous plaques on buttocks, knees, elbows, hands
o Common to all variants
 Erythema, scale, thickening that corresponds to dilated capillaries
 Epidermal acanthosis (thick plaques)
 Abnormal keratinization
 Auspitz sign: punctate bleeding spots when psoriasis scales are scraped off (d/t dilates BV in papillary dermis)
o Foot psoriasis
o Geographic tongue – benign psoriatic glossitis (tongue psoriasis)
o Paraketaosis: scales have retention of nuclei
- Several variants of Psoriasis  plaque, guttate, erythrodemic, pustular
o Guttate Variant: common in children, teardrop-shaped lesions, preceding URI in 66% (like Strep, so check ASLO) … can
spontaneously remit (so they don‟t have Psoriasis for life)
- Investigations  biopsy generally not required

- Treatment→ goals are to  co-stimulatory signal and  TNF

o Embrel (Etanercept)  fusion protein – soluble TNF receptor, Fc human IgG1
 Approved for: treatment of psoriasis, psoriatic arthritis, RA, JRA, ankylosing spondylitis
o Topical steroids (anti-inflamm)
o Retinoids (regulate growth & terminal differentiation of keratinocytes)
o Phototherapy ( Langerhan Cells and their ability to stimulat Th1 cells)
o Immunosuppressants: MTX, Cyclosporine
 Terms
• Dermatophyte: Group of closely related filamentous fungi, which may colonize keratin such as the stratum corneum of the
epidermis, hair, nails
• Dermatophytosis: Cutaneous infections of keratinized tissue by the dermatophyte genera of fungi, trichophyton, microsporum,
epidermophyton
• Dermatomycosis: Organisms other than the dermatophytes that may cause deep fungal or systemic infections with cutaneous
manifestations

Dermatophyte Infection
- Most common players  Tinea rubrum (skin & nails); T mentagrophytes, E. floccosum (causes tinea pedis)
- Pathology
o Hyphae in Stratum Corneum
 Spongiosis, papillary dermal edema (2 to inflamm rxn to fungi in Stratum Corneum)
- Presentation
o Scaly erythematous plaques, annular shape
o Factors that indicate Dermatophyte infection
 Inoculum size
 Suitable environment (like hydration, friction, laceration, heat, darkness, occlusion)
 Growth rate of fungus has be to faster than your skin turns over
o Tinea cruris (“Jock Itch”) – diaper rash, could occur in elderly
o Majocchi’s Granuloma: granulomatous lesion of hair follicle, generally associated with T. rubrum (and requires biopsy for dx and
oral anti-fungal for treatment)
o Kerion: boggy, oozing inflamm reaction of the head in response to fungus (tinea capitis)
 Trx with Prednisone to  inflammation
o Tinea Unguium (Onychomycosis, i.e., dermatophyte infection of the nails): fungus of the nail. Nail thickens, becomes more
brittle; fungus lefts plate and creates a potential space there… keratinization develops. This is located distally
 Contrast with nail changes in AIDS, where you have proximal white subungual onychomycosis. Caused by Tinea rubrum,
which is really only seen in the HIV population
o Tinea versicolor: “spaghetti and meatballs” appearance on KOH prep; Malassezia furfur is the organism that causes this skin
hypopigmentation
- Investigations  KOH prep
Chromoblastomycosis (Subcutaneous Mycoses)
- Caused by dematiaceous – a cluster of pigmented fungi. These fungi are isolated from wood, plant debris, or soil
o Distribution of these fungi  mainly Central America, South America, Africa, & Caribbean islands
- Histopathology
o Granulomatous rxn with giant cells
o Fungus appears as brown, spherical cells w/ thick, dark cell walls and coarsely granular & pigmented
o Spores will be found inside the giant cells and are pathognomonic w/ Chromoblastomycosis  called “Copper Pennies” or “Medlar
Bodies”
o Mixed dermal infiltrate, consisting of neutrophils, histiocytes, epithelioid cells, giant cells, lymphocytes, eosinophils, and plasma cells
- Clinical Presentation
o Begins as small, pink, scaly papule or warty growth, and spreads slowly
o Warty papule expands to become nodular, timorous or verrucous like a cauliflower
o Extremities usually become swollen
o Usually affects one leg or foot, but can also affect hand or upper trunk
- Complications  if spreads to lymphatics, then lymphedema (leading toelephantiasis), and rarely, Squamous cell carcinomas in some chronic
lesions
- Diagnosis
o KOH (may show pigmented hyphae)
o Fungal culture
- Treatment
o For superficial infections, trx with topical azole cream
o For tinea capitis and Majocchi‟s granuloma, systemic therapy like Griseofluvin and Itraconazole  po steroids for PTs with Kerion
formation
o For deep fungal infections, surgical excision („debulking‟), Itraconazole, Terbinafine

Systemic Mycoses (Dimorphic Fungi)

- Coccidioidomycosis
- Histoplasmosis
- Cryptococcus
- North American Blastomycosis
- South American Blastomycosis
- Cryptococcus (Yeast only)
Molluscum Contagiousum (Poxviridae, or Pox virus)
- Epidemiology
o Common, benign, self-limited process in children
o Also occurs in adults, usually as STD (located in scrotum, perineum)
o  frequency in immunocompromised PTs, esp HIV+
- Route of Transmission  skin-to-skin contact, fomites (but less common)
- Pathology
o Crateriform, lobular epidermal hyperplasia
o Intracytoplasmic basophilic inclusions (“Molluscum bodies”)
- Presentation
o Pearly-colored, umbilicated (dimpled) papule (means elevated and < 1 cm diam), especially near the eyes at the medial canthus
- Treatment
o Generally, self-limited
o Cyrotherapy, curettage, chemovesicants
o Immiquimod (which is FDA-approved for warts and used off-label for Molluscum)

Human Papillomavirus
- Virus info  family of non-enveloped dsDNA viruses that are resistant to heat & dessication
- Epidemiology
o Cutaneous warts v. common in children 3-12 yo… up to 10% of pop is affect
o Lower genital tract HPV common among adolescents & adults … affects 20 million in US
o Anogenital warts uncommon in pre-pubertal children
 Should consider sexual abuse, esp if child is > 3 yo, perianal and perivulvar location, the mother has no hx of condylomas
 Inoculation at birth
- Commonly induce papilloma (i.e., warts, verrucae) – which are benign proliferations of skin & mucosa

- Many subtypes of HPV with oncogenic potential (to cause cervical CA and penile squamous cell CA)
o HPV 16, 18, 33, 45 are implicated in 80% of worldwide cervical cancers
o Viral proteins E6 and E7 are important in the induction of cervical CA by HPV types 16 & 18 (p53 and Rb gene inhibition)
o Genomic instability and thus, oncogenicity, is promoted by
 Viral pathogenic factors (like integration of HPV DNA)
 Non-viral factors (e.g., smoking, cervical inflamm, parity, long-term OC use, immune suppression)

- Type of wart and HPV strain

o Common warts HPV 2
o Anogenital; Bushke-Lowenstein Tumor HPV 6, 11
o High-risk anogenital/ cervical, Bowenoid papulosis HPV 16, 18
- Route of transmission: contact w/ infected people or contaminated surfaces
o Microabrasions or epidermal defects will enable inoculation
- Pathogenesis
o Reservoir: persons w/ clinical and subclinical infection as well as environment
 Note that ever peri-lesional skin will harbor HPV’s DNA 
 Note that HPV lifecycle can be completed in fully-differentiated squamous epithelia
 Note that HPV needs cell ‘machinery’ to replicate. AND note that HPV DNA is not incorporated but passed on in
extrachromosomal plasmids
o Productive infection is initiated when virus enters 1 target: basal epithelial cells
 Virus matures with upward progression of the skin layer from the basal layer to the outermost layer ( you can have
subclinical lesions w/o obviously manifesting those warts)
 In basal layer, the E genes are transcribed at low levels
o Effective binding and efficient in vitro infection depends on interaction b/t viral L1 (capsid protein) and cell surface Heparan
Sulfate
o At mid-epidermis: you have amplification
o At cornified layer: virus is shed w/ cornified layer with epithelial sloughing at the skin‟s surface
- Contagion is determined by  lesion location, viral load, degree & nature of contact, immunologic status of exposed person

- Histopathology
o Koilocytes, which are a type of dysplastic squamous cell that are large, pale-staining keratinocytes w/ eccentric nuclei surrounded by
perinuclear halo
o Acnthotic epidermis with “church spire” papillomatosis, hyperkeratosis, and vertical tiers of parakeratosis
o Elongated rete ridges that point radially towards center from periphery (contrast with psoriasis and long-wise hyperplasia of rete
ridges)
o Dermal capillary vessels are prominent, occasionally thrombosed

- HPV Host Immune Response

o Persistent HPV infections are common, possibly indicate viral mechanisms that enable evasion of immune surveillance
o Cell-mediated immune response is eventually generated in majority of causes
 2/3 of cutaneous warts regress spontaneously w/in 2 years
- HPV Cutaneous Lesions
o Common warts (Verruca Vulgaris): occur in trauma-prone areas, auto-inoculation that is 2 to scratching; sometimes assoc w/ nail
matrix destruction
o Flat warts (Verruca Planae)
o Butcher’s Warts (verrucous papules or cauliflower-like lesions, usually multiple; located on dorsal or palmar hands. NOT from
meat; usually from cuts)
o Plantar and Palmar Warts: often painful, punctate black dots called “seeds” that are thrombosed capillaries
- HPV Genitomucosal Lesions
o Anogenital warts (Condyloa accuminata, genital, or venereal warts)
 Most commonly d/t HPV 6, 11, 16, 18
 Papules or nodules that involve perineum, genitalia, inguinal fold, mons, pubis, anus
 Can range from 1-3mm sessile papules to large, exophytic, cauliflower-like masses or plaques
 Skin-colored, brown, or whitish
 Internal extension into vagina, urethra, or anus is not uncommon 

- HPV Diagnosis  PE, histopath, PCR, and immunohistochemical detection of HPV structural proteins

- HPV Treatment  will always involve destructive trx since warts are difficult to remove
o Destructive or Ablative therapy (cyrotherapy, curettage or surgical excision, TCA, electrodessication w/ local anesthesia, laser trx)
o Immunotherapy  e.g., Imiquimod (Aldara®)

Herpes Simplex Virus (HSV-1, HSV-2)

- HSV-1, HSV-2, and HHV-3 (VZV) are subclassified as -herpesvirinae
- Pathogenesis
o Acute Infection  virus replicates at the inoculation site (muco-cutaneous surface): primary lesions
o Establishment of latency  virus travels via retrograde axonal transport to neuronal nuclei in regional sensory ganglia
o Reactivation
 Replication resumes  HSV-1: trigeminal ganglia; HSV-2: sacral ganglia
 Newly assembled virus is transported via anterograde axonal transport to site at/ near inoculation
 Cutaneous vesicular lesions
 Occasionally widespread internal organ involvement
 Reactivation rate is determined by
 Quantity of latent viral DNA, viral genes
 Host factors (genetic background and humoral immune response – fatigue)
 Environmental factors (cold, sunlight)
- Histopathology
o Epidermis
 Spongiosis & vesiculation
 Ballooning of keratinocytes
 Nuclear degeneration w/ chromatin margination to form intranuclear eosinophilic inclusion bodies (Cowdry Type A
inclusions)
o Dermis
 Variably dense infiltrate of lymphocytes, neutrophils, and eosinophils
 Vascular changes (like hemorrhagic necrosis)
- Presentation  primary and recurrent vesicular oro-labial and genital eruptions
o HSV-1: does not have to be “above the belt”
 Incidence of 1 infection is maximal during childhood, as 30-60% of children are exposed to virus
 Prevalence  with age (90% of the ppl 50+ years old are seropositive)
o HSV-2: does not have to be “below the belt”
 Primary infection has 0.5-1 million incidence, and this is  dramatically too
 Prevalence in US is 40-60 million; prior to adolescence, it is rare
o Genital Infection
o Disseminated HSV (esp in HIV+ pts)  generalized pustules, erosions, vesicles and ulcerations
o Eczema Herpeticum (Kaposi‟s Varicelliform Eruption)
 Disseminated HSV-1 infection in ppl w/ widespread cutaneous disease – barrier defect  is the bottom line
 Ranges from mild  fatal (i.e., bacterial suprainfection and bacteremia by S. aureus, Streptococcus, and Pseudomonas)
 Lesions shows up in areas of active or recently healed atopic dermatitis (esp face) several days post-exposure to virus
 May progress to umbilicated pustules along w/ high fever & adenopathy
 Viremia and internal organ involvement can be fatal
 Recurrent disease is milder
 Rapid initiation of Acyclovir can be lifesaving
- Diagnosis
o Clinical diagnosis
o Tzanck Smear  multinucleated giant cells are diagnostic (HSV/ VZV), allows for rapid dx, but has low sensitivity
 Don‟t break the vesicle to take fluid; scrape the base of the vesicles w/ a blade and do the Tzanck Smear with that
o Viral culture enables typing of the exact virus, when active lesions are present – has 60-70% sensitivity
HHV-3, Varicella Zoster Virus (VZV)
- HSV-1, HSV-2, and HHV-3 (VZV) are subclassified as -herpesvirinae
- Epidemiology & Info
o 98% of adult population is sero-positive (had chicken pox)
o Varicella = Chicken Pox
 Acute highly contagious exanthema, common in childhood, resulting from 1 infection of susceptible host
 In Immunocompetent children  constitutional sx rare mild and complications are rare
 In adults and Immunocompromised  higher morbidity and mortality
 Generally, a disease of childhood
 Seasonal epidemics: winter and spring in temperate climates
o Zoster = Shingles
 Recurrent localized disease w/ unilateral pain and vesicular eruption, distributed dermatomally
 A result of re-activation of previously-latent virus within sensory ganglia
 If you already had primary Varicella, your lifetime risk of Shingles is 20%
 Generally, a disease of adulthood. Common in elderly
 No seasonal variation
- Pathogenesis: Primary Varicella
o Transmission is via airborne droplets (in fact, 80-90% of household contact acquire the infection)
o Initial viral replication is @ the portal of entry  Primary Viremia
 Virus is cleared by RES, which is the major site of viral replication during remainder of 1120-day incubation period
 Host defenses are overwhelmed w/ consequent Secondary Viremia of much greater magnitude along w/ cutaneous and
systemic sx
 Virus travels to epidermis via invasion of capillary endothelial cells, approx 14-16 days post-exposure
 Virus travels to dorsal root ganglion, where latency is established
- Pathogenesis: Herpes Zoster
o Reactivation is sporadic, infrequent, and related to senescence of cellular immune response assoc w/  age
 Replication within DRG with painful ganglionitis/ neuralgia
 Infectiou VZV spreads down the sensory nerve and is released around sensory nerve endings in skin, where it manifests as
cluster of zoster vesicles
- Clinical Manifestations
o Varicella = Chicken Pox  usually, self-limited and benign course
 Prodrome of mild fever, malaise  contrast w/ Pox virus, in which there is a prodrome of high fever
 Eruption & Lesions evolve over 12-14 hrs into 1-3 mm vesicles
 Buzzword: “dew drops on a rose petal,” which means a vesicle w/ an erythematous base
 Infective until ALL lesions are crusted
 Few several hundred lesions at varying stages
 Oropharynx is commonly involved
 Affects face & trunk  contrast w/ Pox virus, which mostly affects palms and soles
o Zoster = Shingles  resolves w/o sequelae in immunocompetent
 Prodrome is intense pain, pruritus, tingling, & allodynia (painful sensations from non-painful stimuli)
 Painful erutption; grouped vesicles w/ erythematous base are distributed within sensory dermatome, never cross midline!
- Complications
o Varicella
 Bacterial suprainfection w/ consequent scarring
 CNS complication: Reye‟s Syndrome, encephalitis, acute cerebellar ataxia
 For adults: pneumonia that could cause morality if untreated
 Rare: GN, optic neuritis, keratitis, arthritis, myocarditis, pancreatitis, orchitis, hepatitis, vasculitis
 3rd Trimester infections  fetal abnormalities including LBW, cicatricial skin lesions, ocular abnormalities, cortical atrophy,
psychomotor retardation, hypoplastic limbs
o Zoster
 Bacterial suprainfection w/ consequent scarring
 Post-herpetic Neuralgia (PHN) in 10-15%
 Best if treat early antiviral therapy
 Ophthalmic Zoster (7%)
 Risk of subsequent ocular disease
 Classic sign is Hutchinson‟s Sign (vesicles on nose)
 Ramsay-Hunt Syndrome
 Infection of geniculate nerve ganglion w/ ipsilateral facial nerve paralysis
 Vesicles intra- or peri-auricularly or on roof of mouth
 Meningoencephalitis, motor paralysis, pneumonitis, hepatitis
o Disseminated Disease: >20 vesicles outside 1 or adjacent dermatomes and/or visceral involvement 
- Diagnosis (esp need to distinguish VZV from HSV)
o Tzanck and histopathologic findings are indistinguishable!
o Must instead, use  hx, PE, viral culture, DIF, serology, or PCR
Additional HHV Subtypes
HHV-6 and HHV-7 Roseola
HHV-6 or HHV-7 Pityriasis rosea (possibly) Has “heralded patch”
HHV-8 Kaposi‟s Sarcoma 1st lesion is usually on the oral palate. Suspect undiagnosed HIV
Erythema Migrans, i.e., Lyme Disease, (also i.e., Erythema chronicum migrans, Lyme Borreliosis)
- Lyme Disease is a multi-system disease with classic dermatologic findings
- Info about disease
o Vector  Ixodes ticks (but different tick species depending on the region)
o Reservoir Host  white-footed mouse (NE) and wood rat (NW)
o Maintenance, Intermediate Host  deer
- Pathogenesis
o Tick has to be infected with the spirochete Borrelia burgorferi and also has to be present for at least 24 hours. Rate of transmission
 after 48 hrs
 Spirochet OspC (outer surface protein C) enables it to cross the midgut epithelium, enter the hemocoel, and makes it way to
the tick‟s salivary glands
o Spirochete moves throughout ECM, causing expansion of the EM rash  organisms may be found both in the center & periphery of
lesion
o Spirochetes induces TNF production (inflamm, fever)

- Clinical Presentation has 3 stages

1. Early Localized Disease
o Annular erythema (Bull’s Eye Rash) develops @ site of bite from Borrelia-infected tick
 Typically in 7-15 days
 Seen in 60-90% of PTs, and is 1st cutaneous sign of Lyme Disease
o Regional lymphadenopathy
o Multiple 2 lesions can occur from spirochetemia or lymphatic spread
2. Early Disseminated Disease
o Bell‟s Palsy, cranial neuritis
o Arthralgia, arthritis, myositis
o Myopericarditis, pancarditis, tachycardia, AV block
o Regional or generalized lymphadenopathy
o Conjunctivitis, iritis, hepatitis, non-productive cough
3. Chronic Disease
 Encephalopathy, neuropathy, chronic arthritis
 In Europe (the tick is different), the person can develop localized scleroderma: induration and hypopigmentation
- Investigations
o Biopsy is not routine (since it‟s a clinical dx)
o B. burgodorferi has been cultured from skin specimens, but the technique is not readily available
o Serology: IgM  for 2-6 weeks and IgG  for 6 weeks-months
o Silver stain like Warthin-Starry stain is used to detect T. pallidum and can also show spirochetes in the skin. May see plasma cells
- Diagnosis  Clinical Dx based early on the typical early EM rash (in 60-90% of PTs)
- Prophylaxis
o 100 mg Doxycycline b/t 24-48 hrs for adults and children  8 yrs
o 500 mg Amoxicillin is 1st-choice for young kids and pregnant women

Arthropod Bites
- Arthropods includes insect (6 legs) and arachnids (8 legs)
- Pathogenesis  Note that arthropods can also serve as vectors to inoculate infectious agents (e.g., B. borgdoferi)
o Many rxns are mediated Type I (immediate) or Type IV (delayed) hypersensitivity rxns
o Inflamm can result from either
 Toxic (e.g., venom)
 Allergic mechanism (immunologic rxn elicited, involving release of histamine from mast cells)
o Non-immunologic inflammation results from tissue damage or from necrosis (e.g., spider bit by Brown Recluse Spider)
o Human disease is produced by biting or stinging, injecting toxins, burrowing into skin, as vectors for other diseases
o Most bite reactions are d/t host response to antigens present in saliva
- Histopathology
o Spongiosis
o Papillary dermal edema  vesiculation
o Eosinophils admixed w/ lymphocytes
- Presentation
o PTs may be present with single or multiple erythematous papules, urticarial lesions, papulovesicles or vesicles
o “Papular urticaria” (papules are edematous) refers to hypersensivity rxn to certain insect bites, particularly mosquitoes, fleas, mites,
and bedbugs
- Labs, Biopsy, Treatment
o Dx is usually clinical
o 1 therapy is to remove offending insect from environment
o Treat pets & home as required
o Trx with topical steroids and antihistamines
o Most insect bites resolves spontaneously and uneventfully
Scabies
- Epidemiology
o Worldwide occurrences
o Spread by close personal contact, sexual or otherwise. Can also be transmitted by fomites (it can survive for 3 days off of human skin)
o Immunocompromised (elderly, HIV+, transplant) and those with  sensory functions: Crusted Scabies (Norwegian)
- Pathogenesis
o Entire 30-day life cycle is completed in human epidermis
o Usually < 100 mites on infested host , however there may be millions with crusted scabies
- Presentation
o 2-6 week incubation period before immune system becomes sensitized and sx develop in 1 st-time infestation
o 24-48 hr incubation period in subsequent infestations
o Intense Pruritus
o Erythematous papules  burrows w/ commonly associated excoriations, vesicles, eczematous dermatitis and 2 bacterial infection
o Cutaneous lesions are symmetrical, typically involving  interdigital webs, wrists, axillae, genitals, and areolae
- Investigations
o Scabies prep  scalpel or curette w/ mineral oil to scrap skin and inspect those scrapings for mites, eggs, or fecal pellets using light
microscopy
o
- Treatment
o Systemic trx needed for those who are Immunocompromised,  sensory function, or dementia (those who cant‟ register that they feel
itchy)
o Permethrin cream (5%)
o Ivermectin (po), which is avoided in pregnancy and kids
o Wash bedding, clothing and towels with hot water & dry on high heat to  potential fomite transmission
o Treat family members as may be asymptomatic carriers
o “Post-scabetic pruritus” can persist for 2-4 wks post tx

Lice
- Pediculus capitis (head lice)
- Lice are obligate human parasites that feed exclusively on host blood every 4-6 hrs
- Female louse lays eggs close to scalp for warmth
- Transmission: head-to-head contact as well as fomites (but rarely survive if > 24 hrs away from host)
- Primary vectors of disease
o Epidemic typhus (Rickettsia prowazekii)
o Relapsing fever (Borrelia recurrentis)
o Trench fever (Bartonella quintana)
- Treatment
o Permethrin (synthetic pyrethroid) cream – must treat ALL hairy area, shaving is effective; must also treat sexual partners of affect
person
o Malathion (cholinesterase inhibitor)
o Invermectin (oral or topical) – avoid in pregnancy and toddlers
o Treat clothing, bathe the PT, clothing can be fumigated and washed w/ hot water or discarded

Roseola, i.e., Exanthem subitum (‘Sixth Disease’)

- Epidemiology  affects primarily infants and toddlers who appear well despite fever (“otherwise well”)
- Etiology  HHV-6, HHV-7
- Route of transmission  spread by oro-pharyngeal secretions (can be spread by kissing)
- Pathogenesis
o Lymphocytic for CD4+ T cells – virus replicates and spreads
o Latency eventually established, and salivary glands are most common site of recurrence
- Features
o High fever, followed by exanthema (rash) at defervescence
o Neurologic involvement possible (seizures, encephalitis, aseptic meningitis) – HHV-6 can be in endothelial cells of vessels in frontal
lobe
o Viral reactivation in immunosuppressed PTs
- Lab Investigations
o NOT required for dx
o May show leukopenia, thrombocytopenia, atypical monocytes
o Histopathologic studies not specific although HHV-6 can be detected via immunohistochemical staining
o Specific lab techniques for diagnosing
o HHV infections include serologic assays, PCR & immunofluorescence studies
- Diagnose clinically, based on highly febrile prodrome + rash onset
- Treatment
o Supportive (antipyretics during febrile period)
o Currently no established antiviral therapies
o In vitro studies have shown some HHV-6 sensitivity to Gangciclovir and Acyclovir
Rubella (German Measles)
- Pathogenesis
o Togavirus family, Rubivirus genus; ssrna
o Transmission via respiratory droplet
o 1 site of infection is nasopharynx  regional lymph nodes  viremia
- Presentation
o Exanthem of rose-pink macules w/ cephalo-caudal spread – it fades with progression of the spread
 Measles has head-to-toe migration without fading
o Tender lymphadenopathy (esp. occipital, posterior auricular)
o Prodrome has mild fever, URTI sx
o Self-limited in children & adults
o Note that Rubella is one of many possible multiple genital infections  TORCH (toxoplasma, other, Rubella, CMV, HSV), which
causes “blueberry muffin babies”
- Histopathology  superficial perivascular infiltrate w/ mild spongiosis  but this is NON-specific (in Rubeola too)
- Lab Investigations & Diagnosis
o A clinical diagnosis
o  anti-rubella IgM or 4x  IgG antibodies
- Treatment is supportive; prevention is key (MMR vaccine)
o Prenatal testing; a pregnant woman who‟s exposed should undergo serologic testing

Rubeola (Measles)
- Incidence  with vaccination, esp in the US
- Pathogenesis
o Paramyxovirus family, Rubivirus genus – ssRNA
o Highly contagious & is spread via resp droplets
o Humans are natural host and reservoir of infection
o Viral replication in resp tract‟s epithelial cells  lymphoid tissue & blood  viremia
 Can spread to lungs, liver, and GIT
- Histopathology  superficial perivascular infiltrate w/ mild spongiosis  but this is NON-specific (in Rubella too)
- Presentation
o Incubation period: 10-14 days
o 3 Cs of the prodrome  cough, coryza2, conjunctivitis
o Koplik spots are classic  it is controversial whether or not the rash is result of Ag-Ab complex deposition or direct viral invasion of
tissue
 Genuine macular + popular rash!
o Cephalo-caudal spread without fading
- Complications
o Otitis, pneumonia, encephalitis, myocarditis, and (rare) subacute sclerosing panencephalitis
- Investigations
o Lab dx not necessary
o Can confirm w/ isolating the virus from nasopharyngeal sections, immunofluorescence, or serologic assay
- Treatment
o No specific anti-viral therapy
o Supportive
o Prevention is key (with MMR vaccine)

Etiology Prodrome Rash

Roseola HHV-6, 7 Otherwise well, except Sudden onset following defervescence
dsDNA for high fever
Rubella Togavirus (ssRNA) Fever, URTI, tender Cephalo-caudal spread but fades with
(German lymphadenopathy progression of srpead
Measles)
Rubeola Paramyxovirus (ssRNA) 3 Cs (cough, coryza, Cephalo-caudal spread without fading,
(Measles) conjuncitivitis); fever  exanthem

2
Coryza is inflammation of mucous membranes within nasal cavity; resembles head cold
HIV, AIDS
- Almost all HIV+ pts will develop some disorder during the course of their disease; that‟s why it‟s important to recognized the diff typical and
atypical cutaneous manifestions of the skin diseases that affect this population
- Acute Retroviral Syndrome: seen in 50-90% PTs and about 50-75% will develop a rash
o Earliest cutaneous manifestation in seen during this time
o Characterized by mononucleosis-like syndrome w/ fever, malaise, myalgias, lymphadenopathy
o Most common rash is “morbiliform”
- Severity & extent of HIV-related skin diseases correlates w/  in CD4 counts… early on, they present quite typically but as CD4 # , then the
conditions become more chronic, severe, and resistant to usual therapies
o With CD4  even more, then the skin manifestations are even more unusual  cutaneous Cryptococcus, Kaposi‟s Sarcoma, Bacillary
Angiomatosis
- Infections: generally present when CD4 < 300/mm3
- Most common are muco-cutaneous candidiasis & herpes zoster
- Opportunistic infections begin to develop when CD4 count approaches 200/mm3
o Fungal infections
 Candidiasis  90% of PTs develop thrush
 Intertriginous candidiasis, chronic paronychia3, onychodystrophy, refractory vaginal candidiasis
 Dermatophytes  cutaneous involvement can be atypical, proximal white onychomycosis
o Disseminated fungal infections  Cryptococcus, histoplasmosis, coccidiomycosis, blastomycosis, etc.
 Variable morphology: pustules, papulonodules, patches, plaques, ulcerations… should do Bx or culture
o Bacterial infections  TB, NMTB (atypical TB), Staph, Strep, Bartonella
 Bacillary Angiomatosis  red-to-purple, violaceous vascular-appearing papules or nodules ulcers
 Caused by Bartonella henselae (cat scratches, bites) or Bartonella Quintana (assoc w/ poverty & poor hygiene)
 ( DDX: Kaposi‟s Sarcoma )
o Viral infections 
 Chronic HSV  persistent erosions & ulcerations; consider testing for Acyclovir resistance
 Warts
 Molluscum Contagiosum  favors neck, intertriginous areas; may spontaneously regress when PT is in anti-retroviral
therapy like HAART
 HHV-4  Oral Hairy Leukoplakia in ¼, and this is a predictor of progression to AIDS. The lesions themselves have no
malignant potential
 VZV  HIV+ pts have 7-15x greater relative risk of developing Herpes Zoster; can be multi-dermatomal, ulcerative,
chornic, verrucous  widely disseminated
 May occur as part of IRIS (immune recovery syndrome). (If the person is put on HAART, may have exuberant
response to infection)
 HPV  higher risk of developing CIN & AIN
 More rapid progression from low-grade to high-grade pre-malignant lesions
 Recurrent rates of cervical cancer after standard trx are also higher in those who are HIV+ (compared to those who
are HIV)
o Parasitic infections  scabies, demodex
 Scabies  Crusted (Norwegian): keratotic plaques that may not be pruritic and burrows might not be apparent; can scrape
hyponychium
 Demodicosis  mite that invades follicles on the face, rosacea-like presentation
- Non-infectious cutaneous disorders
o Seborrheic dermatitis  a greasy dermatitis especially affecting the chest & upper back, b/c of the  # sebaceous glands there
o Psoriasis
o Eosinophilic folliculitis  recurrent crops of sterile pustules and papules; pruritus in ½ the PTs
o HIV-associated lipodystrophy
 Not the same as AIDS wasting
 Cushingoid appearance, loss of peripheral fat  buffalo hump
 Visceral fat accumulation
 Hypertriglyceridemia and insulin resistance
 Trx with autologous fat (excise the excess fat and inject it into the sunken cheeks of the AIDS patients), poly-L-lactic acid,
and silicone
o Generalized pruritus
 Switch hypothesis where Th1 cells switch to Th2 cells  Atopic dermatitis, Papular pruritic disorders (i.e. hypersensitivity),
Papular pruritic eruption of AIDS
- Hair & Nails in HIV
o Alopecia 2 to Tinea Capitis
o Telogen effluvium from serious infections w/ fever
o Straighter, softer, silkier, lusterless or dull hair
o Sudden graying of hair
o Proximal white subungal onychomycosis
o Chronic candidiasis
o Melanonychia from Zidovudine
o Beau’s lines (lines and ridges along the length of the nail), psoriatic nail pitting, onycholysis
o Trichomegaly assoc w/ IFN and Zidovudine: elongation of eyelashes

3
Paronychia: infection where the skin meets the nail
- Neoplastic HIV-related Cutaneous Disorders
o In normal population, BCC > SCC, but in HIV+ patients, SCC > BCC
o Kaposi’s Sarcoma
 Seen especially in homosexual men, does NOT correlate w/ amount of immunosuppression
 Cases  with advent of HAART
 Purple papules to plaques with ulcerated nodules
 Initially upper body: along skin lines or trauma sites
 Face, nose, oral mucosa, GI tract and lymphatics
- Adverse Cutaneous drug Eruptions
o Occur more commonly in HIV+ individuals than general population
o Morbilliform eruptions, urticaria, pruritis, vascultive, erythroderma, photodermatitis, SJS, TEN

Photobiology
- UV radiation can be reflected, transmitted, scattered, or absorbed
- For a photobiologic effect, radiation must be absorbed in the stratum corneum and epidermis by chromophores, with absorption in the UVB
range

UV-A
- Contributes to tumor promotion
- May accelerate carcinogenesis
and can induce matrix
metalloproteinases that  tumor
aggressiveness
- Causes more oxidative stress, most
cytotoxic than UVB
- Causes immediate pigment
darkening b/c it photo-oxidizes pre-
existing melanin
UV-B
- Contributes to tumor initiation
- Isomerizes to form Vit D3
- Is the main contributor to erythema
- Causes delayed tanning (visible 72 hrs)
-  melanocyte # and  tyrosinase activity; also, epidermal thickening When UVB is
absorbed, it induces DNA changes (C-T transition mutations, called “UVB
signature”… these are seen in p53 mutations)
- Also induces changes by forming pyrimidine dimers b/t adjacent pyrimidine bases
- UVB absorption also causes trans-urocanic acid to change to cis-urocanic acid
-  Langerhans cells,  suppressor T cells (which induces susceptibility to tumor), 
Th1,  Th2
- Also: mast cell degranulation upon sun exposure… so, some ppl go out into the sun and
they start to itch
- Induces Neoplasia in mice

Skin Cancer Basics

- The #1 cancer in the US, 1 in 5 Americans will develop a skin cancer
o > 90% are caused by sun exposure (UV radiation)
- Most common: BCC > SCC > MM
- Endogenous  genes
- Exogenous  UVR, ionizing radiation, viruses, chemicals (e.g., arsenic, hydrocarbons), chronic irritation, miscellaneous (like burn scars)

Basal Cell Carcinoma Squamous Cell Carcinoma

- Precursor to SCC is Actinic Keratosis
ursor
Prec

- Disruption of Hedgehog-Patched Signaling - Tumor Suppressor  P53 mutation occurs often, PTCH genes
Pathway (PTCH genes) - Also: CDKN2A (cyclin-dependent kinase inhibitor 2A) mutation
Pathogenesis

- P53 mutation occurs often sometimes

- Rarely: CDKN2A - Oncogenes  RAS
- Oncogenes  RAS
- 1st p53 hit leads to AK, and the 2nd hit, p53 mutation, leads to
SCC
- “Rodent Ulcer”: curly papule with central - AK: scaly and erythematous
- Keratinocytes are usually pale, and they‟re normally not
Present.

depression & hemorrhage; looks like rodent took a

Clinical

bite of out it
- Pink or pigmented with brown spots
- Surgical excision (5-yr cure rate of ~90%) - Need to biopsy!
- Micrographic surgery (5-yr cure rate of 99%) - Cyrotherapy: 98.8% cure rate
- Cyrosurgery, radiotherapy, Imiqinod - Topical 5-FU
- Imiquinod, chemical peel (removal of epidermis), curettage
Treatment

- Surgical excision
- Radiotherapy
- Imiquinod
Recurrence potential, & can be locally invasive/ - Prognosis of AK is excellent
disfiguring - 10-yr survival for SCC if regional metastasis is 20% and distant
Prognosis/
course of

metastasis is < 10%

disease
 Melanoma
Precursor to MM is MMIS (Melanoma in situ) from Lentigo Maligna (invasive, vertical growth) from sun-damaged skin

ursor
Prec
- Genetic markers, UV exposure, pigmentary characteristics, #, dysplastic nevi, personal or family hx, upper socioeconomic
Risk
Fact
ors class, immunosuppression
- > 60% arise de novo, but 1/3 are associated w/ nevus remnant (SEE BELOW)
- CDKN2A (cyclin-dependent kinase inhibitor 2A) mutation on Chr. 9q21 significant
Pathoge

- Some mutations of Rb and p53 tumor suppression genes

nesis

- BRAF mutations also

(Tumor initiation, growth, resistance growth, resistance to apoptosis, invasion & metastasis, escape from immune surveillance)
- Architectural pattern
- Asymmetry; Uneven tumor base (except for the nevoid)
- No maturation
Histopathology

- Vary in size & shape

- Lack of cohesion or some nests of melanocytes
- Melanocytes extend down adnexal epith
- Sheets of melanocytes within dermis
- Cytomorphology  atypical melanocytes (pleomorphic nuclei); mitotic figures; necrotic melanocytes
- Other Features  signs of regression, actinic elastosis, non-uniform distribution of melanin, plasma cells at base
Common sites
- White males: back, UPPER extremities
- White females: black, LOWER extremities
- Blacks & Asians: soles, palms, mucous membranes, nail beds

- Superficial spreading: most common type, fair skin; trunk & legs, asymmetric macule; radial growth, seen in repeated
sunburns
- Nodular: grows vertically, 2 nd commonest, 6th decade, M>F, no radial growth; no macular component
- Lentigo maligna: uncommon, 7th decade; face, actinic background and chronic sun exposure; MMIS
- Acral lentiginous: in darker skin types, 7th decade, palms, soles, nail bed.
Clinical Present.

- Variant is Subungual Melanoma: longitudinal pigmentation; Hutchinson‟s sign (pigment in proximal or lateral nail fold)

- Amelanotic Melanoma: no clinically evident pigment; erythematous papule or nodule; diagnostic delay is common
- Ocular Melanoma: rare, can be in conjunctiva or uveal;  risk with DN syndrome and melanosis oculi
- Mucosal Melanoma: rare, in oropharnx or nasopharynx; vagina, anus. Present at advanced stage
- Nevoid Melanoma: clinically indistinct features
- Primary prevention  avoid exposure to UV light, sunscreen use
- Secondary prevention  skin cancer screening, educational campaigns
Trx

- If Stage I,II: surgical excision with local anesthesia

- If further trx after surgical excision is necessary, then IFN, chemotherapy, biologic therapy, etc.
- Mortality less with earlier detection
- While Melanoma is the least common of all the skin cancers, it is responsible for 80% of skin cancer deaths
Prognosis/
course of

- Its incidence it  faster than the other forms

disease

- Prognosis depends on  tumor thickness, ulceration, age, sex, anatomic size, # of lymph nodes involves, side of distant
metastasis
Common Acquire Nevus
- Benign skin neoplasm
- Etiology  not well-understood, but d/t genetic factors (familial clusters) and environmental agents (UV exposure, etc.)
- Pathogenesis
o Melanocytic nevi are thought to originate from melanoblasts, that migrate from neural crest to epidermis
o Nevi are thought to be either hamartomas or benign proliferations w/ some growth advantage over surrounding basilar melanocytes
- Presentation
o May be junctional, intradermal, or compound
o Atypical or “dysplastic” nevi share clinical features of melanoma
o Intradermal nevus: Superficial papillary dermal nests of round pigmented cells & deeper cords of lightly pigmented or nonpigmented
cells
o The person might use SPF, avoid mid-day sun, but has hx of childhood sunburns
- Progression of disease
o Approx 1/3 of melanomas are assoc w/ nevus remnant
- Treatment
o Sun protection, dermascopy, sequential digital imaging
o Remove if  the lesion changes, has atypical clinical appearance, cosmetic reasons, and if it causes repeated irritation

Seborrheic Keratosis
- Epi  uncommon before age 30, possibly AD inheritance
- Presentation  often in sun-exposed area
o Occur on hair-bearing skin
o Face, neck and trunk commonly affected
o Lesions may be yellow, tan, brown
o Keratotic plugging with follicular prominence contributes to stippled texture
o “Sign of Leser-Trélat”
 Abrupt appearance or rapid expansion in number and/or size of SK‟s
 If with pruritus, may suggest the presence of visceral malignancy
 GI adenocarcinoma most common which may have tripe palms and acanthosis nigricans
 Possible that growth factors active in malignant tissues stimulate epithelial hyperplasia
 Non-cancerous states may also be associated with increase in size and number of SK‟s, including psoriasis and pregnancy