SMBM 208

THE INTEGUMENTARY SYSTEM I

The pathophysiology and clinical features of some

common skin diseases:
Acute Inflammatory dermatoses.
Chronic Inflammatory dermatoses.
Bullous dermatoses.
OBJECTIVE:
At the end of this lecture the students will be able to:
•Characterize acute, chronic inflammatory and bullous
dermatoses.
•Explain the pathogenesis.
•Describe the morphological features.
•List the clinical features.
ACUTE INFLAMMATORY DERMATOSES

Urticaria
Urticaria is a common disorder mediated by localized mast cell
degranulation, which leads to dermal microvascular
hyperpermeability. The resulting erythematous, edematous, and
pruritic plaques are termed wheals
PATHOGENESIS
• In most cases, urticaria stems from an immediate (type 1)
hypersensitivity reaction, in which antigens trigger mast cell
degranulation by binding to immunoglobulin E (IgE) antibodies
displayed on the mast cell surface.
• The responsible antigens include pollens, foods, drugs, and insect
venom.
• IgE-independent urticaria may result from exposure to
substances that directly incite mast cell degranulation, such as
opiates and certain antibiotics.
M O R P H O LO G Y
• The histologic features of urticaria are often subtle.
• There is usually a sparse superficial perivenular infiltrate of
mononuclear cells, rare neutrophils, and sometimes eosinophils.
• Superficial dermal edema creates more widely spaced collagen
bundles.
• Degranulation of mast cells, which normally reside around
superficial dermal venules, is difficult to appreciate with routine
hematoxylin-eosin (H&E) stains but can be highlighted using a
Giemsa stain
Clinical Features
• Urticaria typically affects persons between 20 and 40 years
of age, but no age is immune.
• Individual lesions usually develop and fade within hours, but
episodes can persist for days or even months.
• Lesions range in size and nature from small, pruritic papules to
large, edematous, erythematous plaques.
• Increased vascular permeability leads to localized dermal
edema.
• Lesions can be confined to a particular part of the body or
generalized.
Acute Eczematous Dermatitis
• Eczema is a clinical term that embraces a number of conditions
with varied underlying etiologies.
• New lesions take the form of red papules, often with overlying
vesicles, which ooze and become crusted.
• With persistence, these lesions develop into raised, scaling
plaques.
• The nature and degree of these changes vary among the clinical
subtypes.
Clinical subtypes:
• Allergic contact dermatitis, which stems from topical exposure
to an allergen.
• Atopic dermatitis, stem from defects in keratinocyte barrier
function, many with a genetic basis
• Drug-related eczematous dermatitis, a hypersensitivity
reaction to a drug
• Photoeczematous dermatitis, in which eczema appears as an
abnormal reaction to UV or visible light
• Primary irritant dermatitis, which results from exposure to
substances that chemically, physically, or mechanically damage
the skin
Contact dermatitis

• Contact dermatitis is triggered by exposure to an environmental

contact sensitizing agent, such as poison ivy, that chemically
reacts with self-proteins.

• The self-proteins modified by the agent are processed by

epidermal Langerhans cells, which migrate to draining lymph
nodes and present the antigen to naive T cells.
• This sensitization event leads to acquisition of immunologic
memory; on reexposure to the antigen, the activated memory
CD4+T lymphocytes migrate to the affected skin sites.

• There they release cytokines that recruit additional

inflammatory cells and also mediate epidermal damage, as in
any delayed-type hypersensitivity reaction
M O R P H O LO G Y
• In contact dermatitis, the pattern of skin involvement is limited
to sites of contact with the triggering agent, whereas in other
forms of eczema, lesions may be widely distributed.
• Spongiosis characterizes all forms of acute eczematous
dermatitis
• Edema fluid seeps into the epidermis, where it splays apart
keratinocytes.
• Intercellular bridges are stretched and become more
prominent and are easier to visualize.
Eczematous dermatitis.

A, The patterned erythema and scale stems

from a nickel-induced contact dermatitis
produced by this woman’s necklace.

B, Microscopically, there is fluid

accumulation (spongiosis) between
epidermal cells that can progress to small
vesicles if intercellular connections are
stretched until broken.
Clinical Features
• Lesions of acute eczematous dermatitis are pruritic , edematous,
oozing plaques, often containing vesicles and bullae.
• With persistent antigen exposure, lesions may become
progressively scaly (hyperkeratotic) as the epidermis thickens
(acanthosis).
Erythema Multiforme

• Erythema multiforme is an uncommon, usually self-limited

disorder that appears to be a hypersensitivity response to certain
infections and drugs.

• The implicated drugs include sulfonamides, penicillin, salicylates,

hydantoins, and antimalarials.
• Patients present with a wide diversity of lesions (hence called
“multiforme”) including macules, papules, vesicles, and bullae, as
well as characteristic targetoid lesions consisting of red macules or
papules with pale vesicular or eroded centers .

• The epithelial damage is believed to result from the action of

skin-homing cytotoxic T cells that attack the basal cells of the skin
and the mucosae, which may display antigens that cross-react
with the inciting drug or microbe
M O R P H O LO G Y
• Well-developed lesions have a characteristic “targetoid”
appearance .
• Early lesions show a superficial perivascular, lymphocytic
infiltrate associated with dermal edema and margination of
lymphocytes along the dermoepidermal junction in intimate
association with degenerating keratinocytes.
• With time, discrete, confluent zones of basal epidermal necrosis
appear, with concomitant blister formation.
• In the rarer and more severe form of this disease, toxic
epidermal necrolysis, the necrosis extends through the full
thickness of the epidermis.
Clinical Features
• The forms associated with infection (most often herpes virus)
are less severe.
• Erythema multiforme caused by medications can progress to
more serious life-threatening eruptions, such as Stevens-Johnson
syndrome or toxic epidermal necrolysis.
• These forms can be life-threatening because they can cause
sloughing of large portions of the epidermis, resulting in fluid loss
and infections akin to those seen in burn-injured patients.
• These severe forms most often occur as idiopathic reactions to
drugs.
CHRONIC INFLAMMATORY DERMATOSES
Psoriasis
• Psoriasis is a common chronic inflammatory dermatosis.
• Recent epidemiologic studies have shown that psoriasis is
associated with an increased risk of heart attack and strokes, a
relationship that may be related to a chronic inflammatory state.
• Psoriasis is also associated in up to 10% of patients with
arthritis, which in some cases may be severe.
PATHOGENESIS
• Psoriasis is a multifactorial immunologic disease; both genetic
(e.g., human leukocyte antigen [HLA] types) and environmental
factors contribute to risk.
• It is not known if the inciting antigens are self or environmental.
• Sensitized populations of T cells home to the dermis, including
CD4+ TH17 and TH1 cells and CD8+T cells, and accumulate in the
epidermis.
• These cells secrete cytokines and growth factors that induce
keratinocyte hyperproliferation, resulting in the characteristic
lesions.
Clinical Features
• Psoriasis most frequently affects the skin of the elbows, knees,
scalp, lumbosacral areas, intergluteal cleft, and glans penis.
Lichen Planus
• “Pruritic, purple, polygonal, planar papules, and plaques” are
the tongue-twisting Ps that describe this disorder of skin and
squamous mucosa.
• The lesions may result from a CD8+T cell–mediated cytotoxic
immune response against antigens in the basal cell layer and the
dermoepidermal junction that are produced by unknown
mechanisms, perhaps as a consequence of a viral infection or
drug exposure.
M O R P H O LO G Y
• Cutaneous lesions of lichen planus consist of pruritic,
vio-laceous, flat-topped papules, which may coalesce
focally to form plaques.
• These papules are often highlighted by white dots or
lines called Wickham striae.
• Hyperpigmentation may result from melanin loss into
the dermis from damaged cells.
• Microscopically, lichen planus is a prototypical interface
dermatitis,so called because the lesions are concentrated at the
interface of the squamous epithelium and papillary dermis.

• There is a dense, continuous infiltrate of lymphocytes along the

dermoepidermal junction. The lymphocytes are intimately
associated with basal keratinocytes, which often atrophy or
become necrotic.
Clinical Features
• Lichen planus is an uncommon disorder that usually presents in
middle-aged adults.
• The cutaneous lesions are multiple and are usually
symmetrically distributed, particularly on the extremities, and
often occur about the wrists and elbows and on the glans penis.
• In approximately 70% of cases the oral mucosa is also involved.
Lichen Simplex Chronicus
• Lichen simplex chronicus manifests as roughening of the skin,
which takes on an appearance reminiscent of lichen on a tree.
• It is a response to local repetitive trauma such as
continual rubbing or scratching.
• Nodular forms exist that are referred to as prurigo nodularis.
• The pathogenesis of lichen simplex chronicus is not
understood, but the trauma probably induces epithelial
hyperplasia and eventual dermal scarring
M O R P H O LO G Y
• Lichen simplex chronicus is characterized by acanthosis,
hyperkeratosis,and hypergranulosis.
• Also seen are elongation of the rete ridges, fibrosis of the
papillary dermis, and a dermal chronic inflammatory infiltrate
• Of interest, these lesions are similar in appearance to normal
volar (palms and soles) skin, in which skin thickening serves as
an adaptation to repetitive mechanical stress.
BLISTERING (BULLOUS) DISORDERS

• Although vesicles and bullae (blisters) occur as a secondary

phenomenon in several unrelated conditions (e.g., herpes-virus
infection, spongiotic dermatitis), there is a group of disorders in
which blisters are the primary and most distinctive feature.

• Blistering in these diseases tends to occur at specific levels

within the skin, a morphologic distinction that is critical for
diagnosis.
Pemphigus (Vulgaris and Foliaceus)
Pemphigus is a rare autoimmune blistering disorder resulting
from loss of normal intercellular attachments within the
epidermis and the squamous mucosal epithelium.
There are three major variants:
• Pemphigus vulgaris (the most common type)
• Pemphigus foliaceus
• Paraneoplastic pemphigus
PATHOGENESIS

• Both pemphigus vulgaris and pemphigus foliaceus are

autoimmune diseases in which the lesions are caused by
antibody-mediated (type II) hypersensitivity reactions.
• The pathogenic antibodies are IgG autoantibodies that bind to
intercellular desmosomal proteins (desmoglein types 1 and 3) of
skin and mucous membranes.
• The antibodies disrupt the intercellular adhesive function of
the desmosomes and may activate intercellular proteases as
well.

•The distribution of these proteins within the epidermis

determines the location of the lesions.
M O R P H O LO G Y

• Pemphigus vulgaris, by far the most common type, involves

both mucosa and skin, especially on the scalp, face, axillae, groin,
trunk, and points of pressure.
• The lesions are superficial flaccid vesicles and bullae that rupture
easily, leaving deep and often extensive erosions covered with a
serum crust.
• Pemphigus foliaceus, a rare, more benign form of pemphigus,
results in bullae confined to skin, with only infrequent
involvement of mucous membranes.

• The blisters in this disorder are superficial, such that more

limited zones of erythema and crusting of ruptured blisters are
seen.
• The common histologic denominator in all forms of pemphigus
is acantholysis.

• In pemphigus vulgaris, acantholysis selectively involves the

layer of cells immediately above the basal cell layer, giving rise
to a supra-basal acantholytic blister.

• In pemphigus foliaceus, acantholysis selectively involves the

superficial epidermis at the level of the stratum granulosum.
Clinical Features
• Pemphigus vulgaris occurs most commonly in the elderly and
more often in women than men.
• Lesions are painful, particularly when ruptured, and secondary
infections are common.
• Most cases are associated with oropharyngeal involvement at
some point in their course.
• Medications can cause pemphigus, and when they do, patients
most often present with pemphigus foliaceus rather than
pemphigus vulgaris.
Bullous Pemphigoid
Bullous pemphigoid is another distinctive acquired blistering
disorder with an autoimmune basis.
PATHOGENESIS
• Blistering in bullous pemphigoid is triggered by the linear
deposition of IgG antibodies and complement in the epidermal
basement membrane.
• Reactivity also occurs in the basement membrane attachment
plaques (hemidesmosomes), where most of the bullous
pemphigoid antigen (type XVII collagen) is located. This protein
normally is involved in dermoepidermal adhesion.
• IgG autoantibodies to hemidesmosome components fix
complement and cause tissue injury by recruiting neutrophils
and eosinophils.
M O R P H O LO G Y

• Grossly, the lesions of bullous pemphigoid appear as tense

bullae, filled with clear fluid, on normal or erythematous skin.

• Bullous pemphigoid is characterized by sub-epidermal

nonacantholytic blisters.
• Early lesions show a perivascular infiltrate of lymphocytes and
variable numbers of eosinophils, occasional neutrophils,
superficial dermal edema, and associated basal cell layer
vacuolization.
• The vacuolated basal cell layer eventually gives rise to a fluid-
filled blister.
• The blister roof consists of full-thickness epidermis with intact
intercellular junctions, a key distinction from the blisters seen in
pemphigus.
B, Gross appearance of characteristic tense, fluid-filled blisters.
C, A subepidermal vesicle with an inflammatory infiltrate rich in
eosinophils.
Clinical Features
• The bullae do not rupture as readily as in pemphigus and, if
uncomplicated by infection, heal without scarring.
• The disease tends to follow a remitting and relapsing course and
responds to topical or systemic immunosuppressive agents.
• Gestational pemphigoid is a clinically distinct subtype that
appears suddenly during the second or third trimester of
pregnancy.
• It typically resolves after childbirth, but may recur with future
pregnancies
Dermatitis Herpetiformis
• Dermatitis herpetiformis is another type of autoimmune
blistering disorder characterized by extremely pruritic urticaria
and grouped vesicles.
• The disease affects predominantly males, often in the third and
fourth decades of life.
• In up to 80% of cases, it occurs in association with celiac
disease.
•Like celiac disease, dermatitis herpetiformis responds to a
gluten-free diet
PATHOGENESIS
• The strong association of dermatitis herpetiformis with celiac
disease provides a clue to its pathogenesis.
• Genetically pre-disposed persons develop IgA antibodies to
dietary gluten (derived from the wheat protein gliadin) as well
as IgA auto-antibodies that cross-react with endomysium and
tissue transglutaminases, including epidermal transglutaminase
expressed by keratinocytes.
• The resultant injury and inflammation produce a subepidermal
blister.
M O R P H O LO G Y
• The lesions of dermatitis herpetiformis are bilateral, sym-
metric, and grouped and preferentially involve the extensor
surfaces, elbows, knees, upper back, and buttocks.
• Initially, neutrophils accumulate selectively at the tips of
dermal papillae, forming small microabscesses.
• The basal cells overlying these microabscesses show
vacuolization and focal dermoepidermal separation that
ultimately coalesce to form a true subepidermal blister.
B, Lesions consist of intact and eroded (usually scratched) erythematous blisters, often
grouped (seen here on elbows and arms).
C, The blisters are associated with basal cell layer injury, initially caused by accumulation of
neutrophils (microabscesses) at the tips of dermal papillae.