15
Degenerative Diseases and
Perforating Disorders
MICHAEL K. MILLER ROBERT J. FRIEDMAN and EDWARD R. HEILMAN
INTRODUCTION
The disorders in this chapter involve mostly the connective tissue structures of the skin and may rather loosely be
described as “degenerative.” Solar elastosis, for example,
occurs as the result of chronic exposure to solar radiation
and could therefore be regarded as a response to injury,
rather than a degenerative condition. This process results
in an increase in the amount of elastic tissue rather than a
decrease as occurs in normal aging. Nevertheless, it seems
natural to group these disorders together as they tend to
present with alterations of the normal connective tissue
architecture that result in loss of structure and often in
functional or cosmetic abnormalities. In addition, many
of them have the same overlapping differential diagnosis. Therapeutic management of these lesions also tends
to overlap or to be similar among the various conditions,
although in most cases, these therapeutic options have not
been subjected to evidence-based scrutiny, and in many
conditions therapeutic intervention is unnecessary except
perhaps for cosmetic reasons or for patient reassurance.
SOLAR (ACTINIC) ELASTOSIS
Senescent changes in areas of the skin not regularly exposed
to sunlight manifest themselves clinically only in thinning
of the skin and a decrease in the amount of subcutaneous fat. In contrast, there are often pronounced changes in
the appearance of the sun-exposed skin of elderly persons,
especially those with fair complexions. These changes,
however, are the result of chronic sun exposure (photoaging) rather than of intrinsic (chronologic) aging.
Clinical Summary. In exposed areas, especially on the
face, the skin shows wrinkling, furrowing, and thinning.
In addition, there may be an irregular distribution of pigment. Chronic sun exposure may also lead to more fragile
skin and increased areas of purpuric ecchymoses.
Histopathology. In skin not regularly exposed to sunlight, there is a progressive loss of elastic tissue in the
papillary dermis with age. Elastic fibers in the papillary
dermis are composed of elaunin and oxytalan fibers.
Elaunin fibers, which consist of microfibrils and a small
amount of ­elastin, run parallel to the dermoepidermal
junction. Overlying oxytalan fibers, composed solely of
microfibrils, form a thin, superficial network perpendicular to the dermal–­epidermal junction which ends at the
basement membrane zone (Chapter 3). In middle age, the
oxytalan fibers in the papillary dermis are split and fewer
than at a young age, and in old age they may be absent (1).
Mature elastic fibers in the reticular dermis also undergo
changes due to intrinsic aging, becoming fragmented and
porous (2).
In the skin of the face exposed to the sun, especially
in persons with fair complexions, hyperplasia of the elastic tissue is usually evident on histologic examination, by
the age of 30, even though clinically the skin may appear
normal. No white person past 40 years of age has normal
elastic tissue in the skin of the face (3). The elastic fibers
of the reticular dermis are increased in number, and they
are thicker, curled, and tangled.
In patients with clinically evident solar elastosis of the
exposed skin, staining with hematoxylin–eosin reveals, in
the upper dermis, basophilic degeneration of the collagen
separated from a somewhat atrophic epidermis by a narrow band of normal collagen. In the areas of basophilic
degeneration, the bundles of eosinophilic collagen have
been replaced by amorphous basophilic granular material.
A grading scheme for solar elastosis (i.e., chronic
solar damage, CSD) has been developed, validated, and
illustrated, and the grades are defined as follows: CSD 0,
absence of elastotic fibers discernible at 200× magnification; CSD 1 (mild solar elastosis), scattered elastotic fibers
lying as individual fibers, not as bunches in the reticular
dermis; CSD 2 (moderate), densely scattered elastotic fibers
distributed predominantly as bunches; CSD 3 (severe),
amorphous deposits of blue-gray material with lost fiber
texture. CSD defined in this way correlates negatively with
the frequency of BRAF mutations in melanomas and with
the role of the MC1R or melanocortin receptor in relation
to the risk of developing melanoma (4).
With elastic tissue stains, the areas of basophilic
degeneration stain like elastic tissue and therefore are
referred to as elastotic material. The elastotic material
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A
B
Figure 15-1 Solar (actinic) degeneration. A: In the upper dermis, separated from the epidermis by a narrow band of normal collagen,
there are aggregates of thick, interwoven bands of the elastotic material. B: Extensive amorphous material can be seen around and
among elastic and collagen fibers.
usually consists of aggregates of thick, interwoven bands
in the upper dermis (Fig. 15-1A) (5); but in areas of severe
solar degeneration, the elastotic material may have an
amorphous rather than a fibrous appearance (Fig. 15-1B)
and may extend into the lower portions of the dermis
rather than being confined to the upper dermis (6).
On staining with silver nitrate, the distribution of
melanin in the basal cell layer may appear irregular, in
that areas of hyperpigmentation alternate with areas of
hypopigmentation (6).
Pathogenesis. Electron microscopic examination of areas
of solar elastosis shows elastotic material as the main
component (EM 13). Even though this elastotic material resembles elastic tissue in its chemical composition,
it differs significantly in appearance from aged elastic
fibers in unexposed, aged skin. Instead of showing amorphous electron-lucent elastin and aggregates of electrondense microfibrils (Chapter 3), the thick fibers of elastotic
material show two structural components: a fine granular
matrix of medium electron density and, within this matrix,
homogeneous, electron-dense, irregularly shaped inclusions (7). Microfibrils such as those observed in normal or
aged elastic fibers are absent. Immunoelectron microscopy
shows that the elastotic material has retained its antigenicity for elastin but not for microfibrils (8). The number and
size of elastotic fibers are greatly increased over the number and size of elastic fibers found in normal or aged skin.
Extensive amorphous material can be seen around the
elastotic fibers and also among the collagen fibrils. Collagen fibrils are diminished in number, with those present
often showing a diminished electron density, a diminished
contrast in cross striation, and a splitting up into filaments
at their ends (9).
Elastotic material is not regarded as a degeneration
product of preexisting elastic fibers. Most current findings indicate that elastotic material is composed primarily
of elastic tissue, much of which may be newly formed as
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the result of an altered function of fibroblasts. Evidence
of transcriptional activation of the elastin gene in biopsied tissue and fibroblast cultures from sun-damaged skin
further supports this. Additional accumulation of elastotic
material may be secondary to a disruption in the balance
between synthesis and degradation of elastin in photodamaged skin (10).
The elastotic material that histochemically stains like
elastic tissue resembles elastic tissue in its chemical composition and its physical and enzymatic reactions. Thus,
the amino acid composition of the elastotic tissue resembles that of elastin and differs significantly from that of
collagen. In particular, the elastotic material, like elastic
tissue, has a much lower content of hydroxyproline than
collagen (11). Moreover, the elastotic material in unfixed
sections shows the same brilliant autofluorescence as do
elastic fibers on examination with the fluorescence microscope (12), and both the elastotic material and elastic tissue are susceptible to elastase digestion (13). The elastotic
material contains a large amount of acid mucopolysaccharides, as indicated by staining with alcian blue. A significant portion of these acid mucopolysaccharides may
be sulfated because prior incubation with hyaluronidase
removes only 50% to 75% of the alcian blue-positive staining. The basophilia of the elastotic material, however, is
not affected by incubation with hyaluronidase (14).
The irregular distribution of melanin in the epidermis observed in some patients with solar degeneration,
when studied by electron microscopy, is found to be
caused largely by an impairment of pigment transfer from
melanocytes to keratinocytes. Although some keratinocytes contain many melanosomes, others contain few or
no melanosomes. The latter are surrounded by dendrites
laden with melanosomes (15).
Differential Diagnosis. For a discussion of differentiation
of solar elastosis from pseudoxanthoma elasticum, see
Chapter 3.
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Principles of Management. Consistent, long-term use of
sunscreens and/or photoprotective clothing reduces solar
elastosis significantly (16). Dermabrasion and long-term
application of retinoic acid can lead to thickening of the
epidermis, which may reduce the clinical appearance of
photoaging (17,18). On certain sites, select lasers may
ameliorate some of the accumulated photodamage as well.
LOCALIZED EXPRESSIONS OF
SOLAR ELASTOSIS
Several clinically distinct forms of localized solar elastosis have been described. In the nuchal region, the skin,
after many years of exposure to the sun, may appear thickened and furrowed. This is referred to as cutis rhomboidalis
nuchae. Elastotic nodules of the ears are localized papular
and nodular forms of solar elastosis usually occurring
on the antihelix (19–22). Severe solar elastosis may also
occur as yellowish plaques associated with small cysts and
comedones. Favre–Racouchot syndrome (nodular elastosis
with cysts and comedones) is an example occurring on
facial skin lateral to the eyes (23,24). A similar condition
occurring on the arms has been termed actinic comedonal
plaques (25–27). Two other types of circumscribed solar
elastosis occurring on the upper extremities are solar elastotic bands of the forearm (5,28) and collagenous and elastotic marginal plaques of the hands (29–36).
Elastotic Nodules of the Ears
Clinical Summary. Elastotic nodules are most often bilateral, small, asymptomatic, pale papules and nodules on
the anterior crus of the antihelix and, occasionally, helix
(21) of the ears (19,20,22).
Histopathology. Irregular elastotic fibers and clumps of
elastotic material are seen in the background of marked
dermal solar elastosis (Fig. 15-2A). The fibers and clumps
can be highlighted with a Verhoeff-van Gieson elastic stain
(Fig. 15-2B) (21).
Differential Diagnosis. Clinically, they may mimic basal
cell carcinomas, amyloidosis, gouty tophi, or chondrodermatitis nodularis helicis (19–22).
Favre–Racouchot Syndrome (Nodular
Elastosis with Cysts and Comedones)
Clinical Summary. Favre–Racouchot syndrome is characterized by yellow plaques with multiple open and cystically dilated comedones. The condition typically affects
the skin lateral to the eyes in elderly males (23,24,37).
However, a case has also been documented on the shoulder (38). Although the condition is usually bilateral, it
may be unilateral (39–41).
Histopathology. Dilated pilosebaceous openings and
large, round, cystlike spaces are lined by a flattened epithelium and represent greatly distended hair follicles (23,24).
Both the dilated pilosebaceous openings and the cystlike
spaces are filled with layered horny material. Vellus hair
shafts and bacteria have been demonstrated within the
spaces as well, suggesting the cystlike spaces may represent closed comedones rather than true infundibular cysts
(42). The sebaceous glands are atrophic. Solar elastosis
often is pronounced (23), but it may be slight or absent
(43). Because the comedones are open, they do not tend
to become inflamed (44) (see section on Acne Vulgaris,
Chapter 18).
Pathogenesis. It is thought to be primarily secondary to
prolonged solar exposure with the formation of comedones facilitated by an extracellular matrix of compromised
structural integrity (2). Smoking may also be a contributing factor in its development (45).
A
B
Figure 15-2 Elastotic nodule of the ear. A: A dome-shaped papule with marked solar elastosis in the dermis and clumped and
irregular eosinophilic material representing degenerated elastic fibers. B: The course, clumped material is highlighted with an elastic
stain.
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Actinic Comedonal Plaques
Clinical Summary. In actinic comedonal plaques, solitary
nodular plaques with a cribriform appearance and comedone-like structures occur, often unilaterally, on the arms
or forearms (25–27). The plaques are composed of confluent erythematous to bluish papules and nodules. The
condition has been described in fair-skinned individuals
with a history of chronic sun exposure. They can be found
in association with Favre–Racouchot syndrome and may,
in fact, represent an ectopic expression of this entity (26).
Histopathology. Dilated
corneocyte-filled
follicular
lumina are present within areas of elastotic, amorphous
material. The overlying epidermis is usually dyskeratotic
and atrophic. The histologic findings are quite similar to
those seen in Favre–Racouchot syndrome (25,26).
Solar Elastotic Bands of the Forearm
Clinical Summary. Solar elastotic bands of the forearm
consist of soft cordlike plaques across the flexor surface
of the forearms (5,28). The bands occur in areas of actinic
damage and usually with senile purpura.
Histopathology. Nodular collections of basophilic
homogenous amorphous material underlying an atrophic
epidermis are conspicuous features. Thickened degenerated elastic fibers within the homogenous material are also
observed. Stellate fibroblasts and a perivascular infiltrate
of lymphocytes and hemosiderin-laden macrophages are
found in close apposition to the elastic fibers. The nodular collections and thickened elastic fibers stain positively
with Verhoeff-van Gieson elastic stain (5).
Collagenous and Elastotic Marginal Plaques
of the Hands
Collagenous and elastotic marginal plaques of the hands
have been described by several names: elasto-collagenous
plaques of the hands (29), degenerative collagenous
plaques of the hands (30,32), and keratoelastoidosis marginalis (31).
Clinical Summary. This acquired, slowly progressive
condition is usually seen in elderly males and consists of
groups of linear confluent papules along the medial and
lateral aspects of the hands at the juncture of the palmar and dorsal surfaces. The medial aspect of the thumb
and radial aspect of the index finger are most commonly
affected. The condition closely resembles the genodermatosis, acrokeratoelastoidosis (34). However, there is no
familial predisposition or involvement of the plantar surfaces (31,46,47).
Histopathology. The reticular dermis displays an acellular zone of haphazardly arranged collagen with some
bundles running perpendicular to the epidermis (32). The
bundles of collagen are admixed with fragmented elastic
fibers and distinctive angulated amorphous “basophilic
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elastotic masses” in the upper dermis. These masses can
be demonstrated to contain degenerating elastic fibers and
calcium (33).
Pathogenesis. Actinic damage and chronic repetitive
pressure or trauma has been implicated in its pathogenesis
(31,46,47).
PERFORATING DISORDERS
The perforating disorders comprise a group of disorders
sharing the common characteristic of transepidermal
elimination (TEE). This phenomenon is characterized by
the elimination or extrusion of altered dermal substances
and, in some cases, by such material behaving as foreign
material.
Traditionally, four diseases have been included in this
group: Kyrle disease (hyperkeratosis follicularis et parafollicularis in cutem penetrans), perforating folliculitis,
elastosis perforans serpiginosa (EPS), and reactive perforating collagenosis (RPC). A fifth entity, acquired perforating
dermatosis (APD), which is usually associated with renal
disease and/or diabetes mellitus, in which clinical and
histologic findings may resemble any of these four diseases, has been added to this group (48). Although TEE
is a prominent feature in all these conditions, it has also
been described as a secondary phenomenon in other entities, including such inflammatory disorders as granuloma
annulare, one variant of pseudoxanthoma elasticum, and
chondrodermatitis nodularis helicis. Elastic fibers can
be transepidermally eliminated overlying sites of healing
wounds. Collagen may be eliminated through keratoacanthomas (49). Needless to say, there is a long list of other
conditions that can exhibit TEE as an associated reaction
pattern.
Kyrle Disease
Kyrle disease is a rare disorder, described by Kyrle in 1916
(50). There is controversy as to whether it represents a
distinct entity, an exaggerated form of perforating folliculitis (50,51), or whether it actually comprises a group of
disorders with similar epidermal–dermal reaction patterns
associated with chronic renal failure, diabetes, prurigo
nodularis, and even keratosis pilaris. Therefore, the discussion of Kyrle disease and perforating disorders seen
in chronic renal disease and/or diabetes has a very broad
overlap in terms of their clinical and pathologic features.
Clinical Features. This eruption presents with a large
number of papules, some coalescing into plaques, numbering in the hundreds and often distributed on the extremities. Although some may appear to involve the follicular
units, these lesions are more likely to be extrafollicular.
The typical patient is young to middle-aged and often
has a history of diabetes mellitus. The papules are dome
shaped, 2 to 8 mm in diameter, with a central keratotic
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plug. Excoriations often are found in the vicinity of these
lesions. Linear lesions related to possible koebnerization
have been described.
Histopathology. The essential histopathologic findings
include (a) a follicular or extrafollicular cornified plug
with focal parakeratosis embedded in an epidermal invagination, (b) basophilic degenerated material identified in
small collections throughout the plug, with absence of
demonstrable collagen and elastin, (c) abnormal vacuolated and/or dyskeratotic keratinization of the epithelial
cells extending to the basal cell zone, (d) irregular epithelial hyperplasia, and (e) an inflammatory component that
is typically granulomatous with small foci of suppuration
(Fig. 15-3). In most instances, it is important to perform
elastic tissue stains and even trichrome stains to exclude
perforating elastic fibers, as in EPS, or collagen fibers, as
in RPC (52).
Pathogenesis. The primary event is claimed to be a disturbance of epidermal keratinization characterized by the
formation of dyskeratotic foci and acceleration of the process of keratinization. This leads to the formation of keratotic plugs with areas of parakeratosis (53–55). Because
the rapid rate of differentiation and keratinization exceeds
the rate of cell proliferation, the parakeratotic column
gradually extends deeper into the abnormal epidermis,
leading in most cases to perforation of the parakeratotic
column into the dermis. Perforation is not the cause of
Kyrle disease, as originally thought (50), but rather represents the consequence or final event of the abnormally
sped-up keratinization. This rapid production of abnormal
Figure 15-3 Kyrle disease. A large parakeratotic plug containing
basophilic debris lies within an invagination of the epidermis.
The underlying dermis displays acute and chronic inflammation.
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keratin forms a plug which acts as a foreign body, penetrating the epidermis and inciting a granulomatous inflammatory reaction. A certain similarity exists between the
parakeratotic column in Kyrle disease and that observed in
porokeratosis of Mibelli (54). In both conditions, a parakeratotic column forms as the result of rapid and faulty
keratinization of dyskeratotic cells, but, whereas in Kyrle
disease the dyskeratotic cells are often used up so that
disruption of the epithelium occurs, the clone of dyskeratotic cells can maintain itself in porokeratosis of Mibelli by
extending peripherally.
Differential Diagnosis. See Table 15-1.
Principles of Management. Patients may experience
reduced pruritus and decreased lesion symptomatology
with regular renal-replacement therapy when the condition occurs in the setting of end-stage renal disease. Other
treatment modalities are generally supported by case
reports and anecdotal evidence, but may include topical
anti-inflammatory or antipruritic agents, including topical corticosteroids, or, in some cases, topical retinoids.
Limited lesions may respond to local destructive methods,
including cryotherapy.
Perforating Folliculitis
Perforating folliculitis is a perforating disorder that has
many features overlapping with Kyrle disease and also
comprises one of the clinical and histologic patterns seen
in APD.
Clinical Summary. As described by Mehregan and ­Coskey
(56), this is a relatively uncommon disorder u
­sually
observed in the second to fourth decades and is characterized by erythematous follicular papules with central keratotic plugs. The lesions are 2 to 8 mm in diameter and tend
to be localized to the extensor surfaces of the extremities
and the buttocks. The key to making this diagnosis is the
clinical and histologic identification of a follicular unit as
the primary site for the inflammatory process.
Histopathology. The main pathologic abnormalities consist of (a) a dilated follicular infundibulum filled with compact ortho- and parakeratotic cornified cells (Fig. 15-4A);
(b) degenerated basophilic staining material, composed of
granular nuclear debris from nuclear neutrophils, other
inflammatory cells, and degenerated collagen bundles
(Fig. 15-4B); (c) one or more perforations through the
follicular epithelium; and (d) an associated perifollicular
inflammatory cell infiltrate composed of lymphocytes,
histiocytes, and neutrophils. Additionally, altered collagen and refractile eosinophilically altered elastic fibers are
found adjacent to the sites of perforation. When serial sections through the specimen are examined, a remnant of
the hair shaft can sometimes be found.
Pathogenesis. Perforating folliculitis is the end result of
abnormal follicular keratinization most likely caused by
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Table 15-1
Differential Diagnosis of Perforating Disorders
Disease
Primary Defect
Distinctive Features
Histogenesis
Kyrle disease
Focus of dyskeratotic rapidly proliferating cells in the
epidermis
Disturbance of keratinization, forming a plug that
acts as a foreign body
­penetrating the epidermis
and inciting a granulomatous inflammatory reaction
Perforating folliculitis
Hyperkeratotic plug in follicular unit containing a retained
hair
Elastosis perforans
serpiginosum
Formation of numerous coarse
elastic fibers in the ­superficial
dermis
RPC
Subepidermal focus of altered
collagen caused by trauma
Acquired perforating
disorder
Chronic rubbing due to pruritis, resulting in hyperkeratosis,
keratosis, and perforation, possibly in association with other
factors such as accumulation of
poorly dialyzable substances
Follicular or extrafollicular
cornified plug embedded in
an epidermal invagination
associated with epithelial
hyperplasia and absence of
demonstrable collagen and
elastin
Compact ortho- and parakeratotic plug with degenerated collagen, altered
elastin, and mixed inflammatory cell infiltrate, including neutrophils
Formation of narrow channel through an acanthotic
epidermis with elimination
of eosinophilic elastic fibers
Formation of cup-shaped
vertically-oriented channel
with TEE of degenerated
collagen
A combination of features
similar to any of the above
disorders
irritation, either chemical or physical, and even chronic
rubbing. A portion of a curled-up hair is often seen close
to or within the area of perforation or even in the dermis,
surrounded by a foreign-body granuloma (55).
A primary irritant causing
follicular hyperkeratosis,
resulting in a mechanical
breakdown of the follicle
wall by the hair shaft
Thickened elastic fibers act
as mechanical irritants or
“foreign bodies”
Histochemically altered collagen acts as “foreign body”
Exogenously altered skin
in pruritic diabetes and
patients with chronic renal
disease
Differential Diagnosis. In Kyrle disease, the keratinous
plug may be extrafollicular, the perforation usually is present deep in the invagination at the bottom of the keratinous plug, and no eosinophilic degeneration of elastic
B
A
Figure 15-4 Perforating folliculitis. A: A widely dilated follicular unit contains a mixture of keratin, basophilic debris, inflammatory
cells, and degenerated collagen fibers. B: An area of disrupted follicular epithelium with adjacent associated perifollicular inflammation
and alteration of collagen and elastic fibers.
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fibers is found. In addition, in Kyrle disease, epithelial
hyperplasia is a significant feature. For a discussion of the
differential diagnosis of perforating folliculitis from EPS,
see the following section on Differential Diagnosis for
Elastosis Perforans Serpiginosa. See also Table 15-1.
Principles of Management. Treatment of this condition is
similar to that of Kyrle disease, discussed above.
Elastosis Perforans Serpiginosa
EPS is the most distinctive of the perforating disorders
because it demonstrates the best example of TEE. In EPS,
increased numbers of thickened elastic fibers are present
in the upper dermis and altered elastic fibers are extruded
through the epidermis.
Clinical Summary. EPS is a rare disorder that affects
young individuals with a peak incidence in the second
decade. Men are affected more often than women. It is primarily a papular eruption localized to one anatomic site
and most commonly affecting the nape of the neck, the
face, or the upper extremities. The papules are typically 2
to 5 mm in diameter. These papules are arranged in arcuate or serpiginous groups and may coalesce; there is often
mild perilesional inflammation and erythema.
Of particular importance is the association of EPS
with systemic diseases. These associations include Down
syndrome, Ehlers–Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, and Marfan syndrome.
In addition, on rare occasions EPS is observed in association with Rothmund–Thompson syndrome or other connective tissue disorders, and as a secondary complication
of penicillamine administration.
Histopathology. The essential findings include a narrow
transepidermal channel that may be straight, wavy, or of
corkscrew shape, and thick, coarse elastic fibers in the
channel admixed with granular basophilic staining debris
(Fig. 15-5A, B). A mixed inflammatory cell infiltrate
accompanies the fibers in the channel. Also observed are
abnormal elastic fibers in the upper dermis in the vicinity
of the channel. In this zone the elastic fibers are increased
in size and number. As these fibers enter the lower portion of the channel, they maintain their normal staining
characteristics, but as they approach the epidermal surface
they may not stain as expected with elastic stains (57).
Pathogenesis. The cause of EPS is not known. Because the
elastic fibers show no obvious abnormality within the dermis
except hyperplasia, it is conceivable that the thickened elastic fibers act as mechanical irritants or “foreign bodies” and
provoke an epidermal response in the form of hyperplasia.
The epidermis then envelops the irritating material and eliminates it through transepidermal channels. The degeneration
of the elastic fibers within the channels probably is caused by
proteolytic enzymes set free by degenerating inflammatory
cells (57). The channel is formed as a reactive phenomenon
through which the “foreign bodies” are extruded. Because
copper metabolism is essential to the formation of elastin
(58) and because the administration of penicillamine, a copper chelating agent, has been found to induce EPS (59), it
may be suggested that the primary abnormality begins with a
defect in the metabolism of this essential element.
Differential Diagnosis (Table 15-1). Both Kyrle disease and
perforating folliculitis have in common with EPS a central
keratotic plug and a perforation through which degenerated material is eliminated. In addition, perforating folliculitis, like EPS, shows the elimination of degenerated
eosinophilic elastic fibers. However, neither of the two
diseases shows the great increase in elastic tissue that is
observed in EPS in the uppermost dermis and particularly
in the dermal papillae on staining with elastic tissue stains.
Principles of Management. Treatment modalities include
local destruction with cryotherapy (60), topical medications
including retinoids, corticosteroids, or salicylic acid, with
rare reports of imiquimod (61) benefiting select patients.
Systemic treatment can include retinoids (62). Other locally
destructive methods may be considered in select cases.
Reactive Perforating Collagenosis
RPC is a rare perforating disorder in which altered collagen is extruded by means of TEE. True, classic RPC is
B
A
Figure 15-5 Elastosis perforans serpiginosa. A: A portion of a narrow curved channel through an acanthotic epidermis is shown. B:
The lower portion of the channel contains coarse elastic fibers and basophilic debris.
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a genodermatosis that is inherited as an autosomal dominant or recessive trait (63,64). The lesions are precipitated
by trauma, arthropod assaults, folliculitis, and even exposure to cold. RPC occurs early in life, and both genders
are equally affected. An adult, acquired type of RPC has
been described in association with diabetes mellitus and
chronic renal failure (65–67) and may be best interpreted
as an expression of APD (see text following).
Clinical Summary. The primary clinical lesion is a small
papule that enlarges to the size of 5 to 10 mm with a
hyperkeratotic central umbilication. Often the lesion
appears eroded. These lesions spontaneously regress, leaving superficial scars with postinflammatory pigmentary
alteration. Koebnerization is common.
Histopathology. The classic lesion shows a vertically-oriented, shallow, cup-shaped invagination of the epidermis,
forming a short channel (Fig. 15-6A). The channel is lined
by acanthotic epithelium along the sides. At the base of the
invagination there is an attenuated layer of keratinocytes
that in some foci appear eroded. Within the channel there
is densely packed degenerated basophilic staining material
and basophilically altered collagen bundles. Vertically-oriented perforating bundles of collagen are present interposed between the keratinocytes of the attenuated bases
of the invagination (Fig. 15-6B). It is important that a
Masson-trichrome stain be done to confirm that the fibers
are collagen.
Pathogenesis. The basic process in RPC consists of the
TEE of histochemically altered collagen. Nevertheless,
as delineated by electron microscopy, the collagen fibrils
appear intact, with regular periodicity (68).
Differential Diagnosis. See Table 15-1.
Principles of Management. Topical retinoic acid and
narrow-band ultraviolet B phototherapy have been successfully used to treat familial cases (69). See also the following Principles of Management section for APD.
Acquired Perforating Dermatosis
This term was suggested by Rapini et al. (48) to describe
a pathologic process encompassing the various forms of
TEE seen in patients with renal disease and/or diabetes
mellitus. Differences in clinical and histologic features,
such as the presence of koebnerization, or histologic evidence of follicular involvement with or without collagen
fibers in the epidermis have variably led to diagnoses of
Kyrle disease, “acquired” RPC, or perforating folliculitis.
Other terms that have been used include perforating disorder secondary to chronic renal failure and/or diabetes
mellitus, perforating folliculitis of hemodialysis, Kyrlelike
lesions, and uremic follicular hyperkeratosis (70-72).
Clinical Summary. Lesions are frequently pruritic, and
range from hyperkeratotic papules and nodules resembling Kyrle disease to RPC-like umbilicated papules, nodules, and plaques to erythematous, follicular papules and
nodules mimicking perforating folliculitis (48,49,72).
Annular plaques and erythematous pustules have also
been described, with histologic features of RPC and perforating folliculitis, respectively (72). The most common
location is the extensor surfaces of the extremities, especially lower, but the trunk and head can also be involved
(48,72). APD has also been described in renal disease
secondary to chronic nephritis, obstructive uropathy,
anuria, and hypertension-related nephrosclerosis (49).
Cases of APD have also been reported in patients with
lymphoma, AIDS, hypothyroidism, hyperparathyroidism,
and associated with pruritis secondary to liver disease,
neurodermatitis, “atopic dermatitis” and malignant neoplasia (48,73).
Histopathology. As mentioned, the histologic features of
APD are variable, even within different lesions from the
same patient. When vertically-oriented, Masson-trichrome
positive collagen bundles are present within a perforation,
the findings are suggestive of RPC. When perforation is
associated with a follicle, the findings resemble perforating
A
B
Figure 15-6 Reactive perforating collagenosis. A: A shallow cup-shaped invagination of the dermis containing a mixture of
basophilic material and degenerated collagen bundles. The adjacent epidermis displays acanthosis. B: Vertically-oriented perforating
bundles of collagen are present at the base of the invagination.
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folliculitis. However, chronic rubbing can lead to superimposed features of prurigo nodularis, distorting the follicle and making it unrecognizable. TEE in the absence of
follicular involvement, without demonstrable collagen or
elastin, is reminiscent of Kyrle disease. Perforation associated with EVG-positive elastic fibers within a transepidermal canal, as seen in EPS, has also been described (72,74).
Patterson et al. (75) reported a patient who had multiple
lesions biopsied which variably showed histologic features
of RPC, perforating folliculitis, and Kyrle disease. Combined TEE of both elastic and collagen fibers have been
observed in four patients with renal disease (48), a finding
which has only rarely been described in Kyrle disease or
RPC (70).
Pathogenesis. RPC, EPS, and perforating folliculitis exist
as distinct perforating disorders when not associated
with renal disease and diabetes. At least in the setting of
APD, however, the presence of various histologic patterns
suggests the possibility of a common underlying mechanism (48). A nearly ubiquitous clinical feature of APD is
pruritis. Certainly, lesions are often distributed in areas
accessible to scratching, and reducing pruritis can lead to
clearance (73). Poor blood supply secondary to diabetic
microangiopathy, combined with trauma, may lead to
dermal necrosis, alteration of connective tissue, and TEE
(70,73,76). Others have suggested that a consequence of
dialysis is the underlying cause of APD (72). Possible etiologies include disruption of metabolism of vitamins A
and/or D (77) or the accumulation of a poorly dialyzable
substance in the dermis (78,79). Fibronectin, a glycoprotein of the extracellular matrix, accumulates in the serum
of uremic and diabetic patients. It has been suggested
that transcriptional induction of fibronectin, possibly
by transforming growth factor beta (TGF-β) or plateletderived growth factor (PDGF), increases epithelial migration and proliferation and leads to TEE (77). APD has
been reported in 5% to 11% of patients with chronic renal
failure undergoing hemodialysis (49,78), and clearance of
APD following renal transplant has been reported. However, it has also occurred following transplant, in patients
with normal renal function (72). In addition, some cases
have occurred prior to the start of hemodialysis or in
patients who never underwent dialysis (49). Patterson
suggests that TEE may represent a “final common pathway” of a variety of dermal and epithelial processes acting
alone or in concert (70).
Differential Diagnosis. See Table 15-1.
Principles of Management. A similar topical approach to
previously discussed diseases may also be reasonable for
limited disease or in some clinical scenarios. In conjunction with treatment of underlying systemic disease, allopurinol, doxycycline, systemic retinoids, and narrow-band
ultraviolet B phototherapy have been effective in treatment
of APD (80).
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PERFORATING CALCIFIC ELASTOSIS
(PERIUMBILICAL PERFORATING
PSEUDOXANTHOMA ELASTICUM)
In perforating calcific elastosis, also referred to as periumbilical perforating pseudoxanthoma elasticum (PPPXE),
a gradually enlarging, well-demarcated, hyperpigmented
patch or plaque is usually seen in the periumbilical region
in middle-aged, obese, multiparous women with hypertension (81).
Clinical Summary. Most patients described have been
African American (82). The patch or plaque is in some
instances atrophic with discrete keratotic papules at the
periphery (83); in other instances, it has a verrucous border (84), and in still others it has a fissured, verrucous
surface throughout (85). Lesions occurring on the breast
have also been described (86–88). Perforating calcific elastosis was initially regarded as EPS coexisting with pseudoxanthoma elasticum (89–93). The disorder was later
shown to be distinct from EPS (84).
Four patients with perforating calcific elastosis associated with renal failure have been described (82,87,94,95).
One patient demonstrated regression of the lesions with
hemodialysis (82).
Histopathology. Numerous altered elastic fibers are
observed in the reticular dermis. They are short, thick, and
curled, and are encrusted with calcium salts, as shown by
a positive von Kossa stain. They are thus indistinguishable
from the elastic fibers seen in pseudoxanthoma elasticum
(81). As in pseudoxanthoma elasticum, the elastic fibers
are visible even in sections stained with hematoxylin–
eosin, owing to their basophilia (83). The altered elastic
fibers in perforating calcific elastosis are extruded to the
surface either through the epidermis in a wide channel
(84), or through a tunnel in the hyperplastic epidermis
that ends in a keratin-filled crater (83) (Fig. 15-7A, B).
Pathogenesis. Electron microscopic examination reveals
electron-dense deposits of calcium primarily in the central core of elastic fibers. Calcification of collagen bundles
is also seen (86). The etiologic nature of perforating calcific elastosis has been debated. Some hypothesize it is
an acquired lesion developing as a consequence of local
cutaneous trauma from such factors as obesity, multiple
pregnancies, ascites, or multiple abdominal surgeries
(81,83,86). They cite the characteristic clinical presentation, lack of systemic manifestations, and absence of
familial predisposition in most cases. The occurrence of
perforating calcific elastosis in patients with renal failure
may suggest that conditions resulting in an abnormal calcium phosphate product may produce abnormal calcification of elastic fibers. The occurrence of pseudoxanthoma
elasticum–like eruptions in patients exposed to saltpeter
(calcium–ammonium–nitrate salts) (96), and in one patient
with chronic idiopathic hyperphosphatasia (97), supports
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B
A
Figure 15-7 Perforating calcific elastosis. A: Degenerating elastic fibers encrusted with calcium salts in the reticular dermis surround
a distorted transepidermal channel. B: The calcified fibers are in the process of being extruded through the base of the channel.
this concept. Others have argued that perforating calcific
elastosis may represent a localized cutaneous expression
of hereditary pseudoxanthoma elasticum (85). Arguments
for the latter theory include a history of hypertension in
75% of reported patients and angioid streaks in one-third of
examined patients (82). The presence of perforation is also
not distinctive as the finding has also been noted to occur
in lesions of classic hereditary pseudoxanthoma elasticum.
The disorder may represent a spectrum ranging from a
purely acquired form with no systemic manifestations to
an inherited form with limited systemic expression.
Principles of Management. Topical fluocinolone acetonide therapy can be of some benefit. Spontaneous resolution without intervention has also been reported (2).
LATE-ONSET FOCAL DERMAL
ELASTOSIS
Clinical Summary. Late-onset focal dermal elastosis has
been described in a small number of elderly patients
with lesions clinically resembling pseudoxanthoma elasticum (2,98–101). Patients present with slowly progressive, asymptomatic 1- to 3-mm yellow papules, in healthy
adults in the seventh to ninth decades. The lesions are distributed predominantly on the neck, thighs, groin, axillae,
and antecubital and popliteal fossae (2,100,101).
Histopathology. Focal elastosis along with an increased
accumulation of normal-appearing elastic fibers in the mid
and deep dermis are seen (98). No pathologic changes of
pseudoxanthoma elasticum are present.
Pathogenesis. There is an increase in elastin and collagen
contents in tested patients as compared with controls. An
increase in elastin, type I and III collagen mRNA’s from
patients’ fibroblasts has been observed. No change in
excreted elastin peptides is noted in affected patients. An
overexpression of elastin has been postulated (102).
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HYPERKERATOSIS LENTICULARIS
PERSTANS (FLEGEL DISEASE)
A rare dermatosis first described in 1958 (103), hyperkeratosis lenticularis perstans is a disorder that starts in late
life and persists indefinitely. An autosomal dominant transmission has been noted in several instances (104–106).
Clinical Summary. Hyperkeratosis lenticularis perstans
consists of asymptomatic, flat, hyperkeratotic papules
from 1 to 5 mm in diameter, located predominantly on
the dorsa of the feet and on the lower legs. Removal of
the adherent, horny scale causes slight bleeding. In addition to the central horny scale, larger papules often have
a peripherally attached collarette of fine scaling. In two
reported instances, extensive papular lesions were present
on the oral mucosa (107). Other reported sites include the
thighs, upper extremities, and ears (108,109). Unilateral
involvement may represent postzygotic mosaicism (110).
Histopathology. In some instances, the histologic picture is
nonspecific, showing hyperkeratosis with occasional areas of
parakeratosis, irregular acanthosis intermingled with areas of
flattening of the stratum malpighii, and vascular dilation with
a moderate amount of perivascular lymphocytic inflammation (111). It seems, however, that if the specimen is obtained
from a well-developed, markedly hyperkeratotic lesion, a
characteristic, although not necessarily diagnostic, histologic
picture may be revealed. The lesion shows a greatly thickened, compact, strongly eosinophilic horny layer standing
out in sharp contrast to the less heavily stained basket-weave
keratin of the uninvolved epidermis (108). The underlying
stratum malpighii appears flattened, with thinning or even
absence of the granular layer (Fig. 15-8).
Acanthosis is observed at the periphery. In some
instances, bordering on the central depression, the epidermis at the periphery forms a papillomatous elevation resembling a church spire (103,112,113). Vacuolar alteration and
apoptotic cells in the basal layer have been seen in some
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importance but can be quite disturbing to those who are
afflicted (125).
Clinical Summary. Striae distensae occur most commonly on the breasts and abdomen, and on the thighs,
buttocks, and in the inguinal region. They are caused by
stretching of the skin that occurs with pregnancy, growth
spurts, obesity, and weight lifting. Use of systemic or local
potent topical steroids can contribute to striae development. They consist of bands of thin, wrinkled skin that at
first are red, then purple, and finally white, with a degree
of atrophy (125).
Figure 15-8 Hyperkeratosis lenticularis perstans. Dense
compact orthokeratosis surmounts an epidermis, with focal
flattening of the stratum malpighii. A lymphocytic infiltrate is
present in the upper dermis.
cases (108,114,115). The dermal infiltrate is composed
largely of lymphoid cells and is located as a narrow band
fairly close to the epidermis with a rather sharp demarcation at its lower border. Immunohistochemical studies have
shown the infiltrate to be predominantly T cells (116–118).
Pathogenesis. Under electron microscopic examination,
the absence of membrane-coating granules was noted in
some cases and regarded as the primary lesion of hyperkeratosis lenticularis perstans (107,106).
A defect in the membrane-coating granules seems
likely to play a role in Flegel disease, because in other
cases in which membrane-coating granules were present, the granules lacked a lamellar internal structure and
appeared vesicular (119,120). In one case, both lamellar
and vesicular bodies were observed, with lamellar bodies greatly predominating in uninvolved epidermis and
vesicular bodies in lesional epidermis (121). However, one
study of lesional skin from four patients found no such
abnormalities in lamellar bodies (122).
Other ultrastructural findings in Flegel disease that
have been described in some cases include Sézary cell–like
lymphocytes (123), rodlike intracytoplasmic inclusions
(124), and wormlike bodies in histiocytes (121). The significance and role of these findings in the etiology of Flegel disease is unknown.
Principles of Management. Treatment of Flegel disease is
often unsuccessful. It is resistant to corticosteroids and
topical keratolytic agents. Dermal abrasion and shave
excision of lesions have been used. Topical 5-fluorouracil
and oral retinoids have provided some benefit, but longterm results are disappointing. Topical retinoids may be of
some benefit (110).
STRIAE DISTENSAE
Striae distensae, often referred to as stretch marks, are a
common cutaneous disorder with no significant medical
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Histopathology. The epidermis is thin and flattened.
There is a decrease in the thickness of the dermis. The
upper portion of the dermis shows straight, thin collagen
bundles arranged parallel to the skin surface and transverse to the direction of the striae. The elastic fibers are
arranged similarly. Fine elastic fibers predominate in early
lesions, whereas in older lesions they are thick (126).
Within the striae, nuclei are scarce and sweat glands and
hair follicles are absent (127).
Pathogenesis. The histologic findings support the view
that striae distensae are scars. They occur in conditions
associated with increased production of glucocorticoids by
the adrenal glands. Among these conditions are pregnancy,
obesity, adolescence, and especially Cushing disease (128).
In obesity, the increased adrenocortical activity is a consequence of the obesity, and the production of glucocorticoids returns to normal when the body weight is reduced
(129). Similarly, the occurrence of striae in nonobese adolescents, as noted in 35% of the girls and 15% of the boys
examined, is associated with an increase in 17-kerosteroid
excretion (130). Striae may also form in response to prolonged intake of corticosteroids or following the prolonged
local application of corticosteroid creams to the skin. The
action of the glucocorticoids consists of an antianabolic
effect suppressing both fibroblastic and epidermal activity,
as tissue culture studies have shown (131).
Principles of Management. The use of topical tretinoin
0.1% cream can improve the appearance of early striae.
Several types of lasers have been used to treat early
striae (125,132,133). Improvement in the leukoderma of
striae alba was noted with a 308-nm excimer laser (133).
­Treatment is generally of limited benefit.
LINEAR FOCAL ELASTOSIS
(ELASTOTIC STRIAE)
Clinical Summary. Linear focal elastosis (elastotic striae)
is an uncommon, but more likely underdiagnosed or underreported, disorder presenting as palpable striaelike yellow
linear bands (2). This disorder was initially described in
the lumbosacral region of elderly males (134). Lesions
on the thigh and legs have also been reported (135,136).
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Occasionally, lesions arise in association with striae distensae (137–140). A number of cases have occurred in
individuals under 30 years of age (141–143).
Histopathology. Abundant fragmented, clumped, and
wavy elastic fibers are present between hypertrophic
collagen bundles in the mid reticular dermis (12,140).
Elongated elastic fibers with split ends resembling a “paintbrush” can be seen (144). A decrease in papillary dermal
elastic fibers has been demonstrated in the elastotic striae
from one patient with coexistent pseudoxanthoma-like
papillary dermal elastolysis (136). Unlike striae distensae,
there is no decrease in thickness of the dermis or atrophy
of the overlying epidermis.
Pathogenesis. Electron microscopic examination reveals
fragmented elastic tissue throughout the dermis (134).
Widespread elastic fiber microfibrils, some occurring in
continuity with intracytoplasmic filaments of fibroblasts,
along with sequential maturation of elastic fibers, have
been observed suggesting an elastogenic process (145).
An increased number of elastic fibers in lesional skin
have also been documented (144). It has been postulated
that elastotic striae may represent a regenerative process
of striae distensae (137,140). This view is supported by
the presence of contiguous striae distensae and elastotic
striae in several patients. Accumulations of thin elastic
fibers have been observed in late stages of striae distensae
(126,127,146). Thus, linear focal elastosis may represent
an excessive “keloidal” repair process occurring in striae
distensae (140).
Principles of Management. There are no known efficacious treatments for this condition.
PSEUDOXANTHOMA ELASTICUM–
LIKE PAPILLARY DERMAL
ELASTOLYSIS
Clinical Summary. Papillary dermal elastolysis, first
described in 1992 (147), is a rare, acquired condition
consisting of soft coalescent yellow-white papules mainly
on the lateral neck and supraclavicular regions of elderly
women (136,147–154, 155). The clinical appearance of the
skin lesions closely resembles those of pseudoxanthoma
elasticum (PXE). However, no other systemic features of
PXE are seen. A similar and possibly related disorder, white
fibrous papulosis of the neck, is characterized by paler, more
discrete and firm papules (156–162). The term fibroelastolytic papulosis of the neck has been suggested to encompass
the spectrum of the two disorders (162).
Histopathology. There is a marked decrease to absence of
elastic fibers in the papillary dermis (147). Focal elastotic
changes in the subpapillary and mid-dermis have also been
demonstrated (163). No calcification or fragmentation
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of elastic fibers is seen. A slight decrease in elastic fibers
along with the presence of thickened collagen bundles in
the papillary dermis are differentiating features in white
fibrous papulosis of the neck (158,162).
Pathogenesis. Electron microscopic examination confirms the absence of elastic fibers in the papillary dermis
along with the presence of immature elastic fibers in the
upper reticular dermis. Fibroblasts with prominent rough
endoplasmic reticulum, with numerous dilatations and
elongated dendritic processes, are present (147,153). In
one patient, formation of loose component fibrils of elastic
fibers and elastophagocytosis were seen ultrastructurally
(151). Papillary dermal elastolysis has been suggested to
be a disorder of intrinsic skin aging due to its histologic
similarity (147). However, immunohistochemical studies
have shown a decrease in both fibrillin-1 and elastin in
affected areas, whereas aged normal-appearing skin demonstrates only a decrease in fibrillin-1. A defect in elastogenesis may contribute to the pathogenesis of the disorder
(147,154). The female predominance and the report of a
familial occurrence may suggest possible genetic factors
(153). Immunohistochemical studies, using an antibody
to serum amyloid component P, which specifically marks
the peripheral mantle of microfibrils of elastic fibers in
adults, underscored the absence of elastic tissue in the
affected papillary dermis (164).
Principles of Management. There are no known efficacious treatments for this condition (155).
MID-DERMAL ELASTOLYSIS
Mid-dermal elastolysis is a rare disorder, first described
in 1977 (165), occurring predominantly on the arms and
trunk of middle-aged women.
Clinical Summary. Three patterns are seen (166). The
type 1 pattern consists of widespread, large areas of fine
wrinkling along skin cleavage lines. The type 2 pattern
consists of small, soft, papular lesions with tiny perifollicular protrusions, leaving the hair follicle itself as an
indented center (167,168). These two patterns may coexist in the same patient. Type 3 presents with persistent
reticulate erythema (166,169). Urticaria (165), erythematous patches (170), or granuloma annulare (171) may precede some of the lesions. These postinflammatory forms of
mid-dermal elastolysis have some similarity to a disorder
first described in young South African girls termed postinflammatory elastolysis and cutis laxa (172–174). In the
latter disorder, widespread wrinkling followed an acute
phase of firm, erythematous, infiltrated lesions. An overlap with another disorder described as disseminated nevus
anelasticus is also likely (175).
Histopathology. In this condition there is a selective
absence of elastic tissue strictly limited to the mid-dermis
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of involved areas (165). The perifollicular protrusions
around indented hair follicles result from preservation of a
thin layer of elastic tissue in the immediate vicinity of the
follicles. This causes the hair follicles to appear retracted
while the perifollicular skin protrudes (167). A mild perivascular inflammatory infiltrate of mononuclear cells with
occasional interstitial multinucleated giant cells exhibiting elastophagocytosis may be seen (176–178). Electron
microscopic examination also reveals fragments of normalappearing elastic fibers within macrophages (176,179).
Pathogenesis. The disorder likely represents a postinflammatory process, although in some cases this may
be subclinical, or remote. Immunohistochemical evidence
of immune activation has been observed in lesional T
lymphocytes and endothelial cells (180). The cytokines
and elastases produced by inflammatory cells along with
elastophagocytosis by macrophages may contribute to the
loss of elastic fibers (176). A possible autoimmune mechanism has been hypothesized based on its associations
with rheumatoid arthritis (181), silicone mammoplasty,
elevated autoantibodies, false positive Lyme titers (182),
lupus erythematosus (183), and Hashimoto thyroiditis
(184). Culture studies performed with dermal fibroblasts
from lesional skin showed an 80-fold increase in elastin
mRNA and a 2-fold increase in elastolysis compared with
normal skin (155). An idiosyncratic reaction to ultraviolet light has also been proposed as an etiologic or exacerbating factor (185,186). Recent studies suggest that UV
exposure may lead to increased expression, by fibroblastlike cells, of elastin-degrading matrix metalloproteinase
MMP-9 (187).
Principles of Management. There are no proven therapeutic regimens. Topical retinoids may improve wrinkling
but do not alter the course of the process. A long list of
treatment options such as colchicine, topical and systemic
steroids, and chloroquine have not produced any benefit (166). Because sun exposure may play a role in the
pathogenesis of mid-dermal elastolysis, photoprotection is
strongly recommended.
MACULAR ATROPHY (ANETODERMA)
Clinical Summary. Atrophic patches located mainly on the
upper trunk characterize macular atrophy, or anetoderma.
The skin of the patches is thin and blue-white and bulges
slightly. The lesions may give the palpating finger the same
sensation as a hernial orifice.
Two types of macular atrophy are generally distinguished: the Jadassohn–Pellizzari type, in which the
atrophic lesions initially appear red and, on histologic
examination, show an inflammatory infiltrate; and the
Schweninger–Buzzi type, which clinically is noninflammatory from the beginning. However, not every case can
be clearly assigned to one or the other of these two types;
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many clinically noninflammatory cases show an inflammatory infiltrate when examined histologically (188). The
justification for distinguishing between the inflammatory
and noninflammatory types has therefore been questioned
(189). In many patients, new lesions continue to appear
over a period of several years. Rare congenital and familial
cases have been reported (190–194).
The so-called secondary form of macular atrophy
occurs in the courses of various diseases, such as syphilis,
lupus erythematosus, tuberculosis, sarcoidosis, and leprosy (195–198). The macular atrophy then represents the
atrophic stage of the preceding disease (199). Other cases
of secondary anetoderma have occurred in association
with porphyria (200), urticaria pigmentosa (201,202),
pilomatricomas (203,204), Down syndrome (205,206),
acrodermatitis chronica atrophicans (189), Takayasu arteritis (207), Graves disease (208), Addison disease (208),
autoimmune hemolysis (208), systemic scleroderma
(208), varicella (209), anticardiolipin and antiphospholipid antibodies (210–216), HIV (217), Sjögren syndrome (218,219), α1-antitrypsin deficiency (213), B-cell
lymphoma (218,220), plasmacytoma (221,222), cutaneous lymphoid hyperplasia (221), angular cheilitis (223),
juvenile xanthogranuloma (224,225), and generalized
granuloma annulare (226). Macular atrophy has also been
observed after iatrogenic procedures such as leech application (227), monitoring electrode placement in premature
infants (228,229), hepatitis B vaccination (230), and after
prolonged treatment with penicillamine (231).
Histopathology. Early, erythematous lesions usually
show a moderately pronounced perivascular infiltrate of
mononuclear cells (232). In a few instances, however, the
early inflammatory lesions show a perivascular infiltrate
in which neutrophils and eosinophils predominate and
nuclear dust is present, resulting in a histologic picture
of leukocytoclastic vasculitis (233,234). Microthrombosis
has also been noted in patients with anetoderma and associated antiphospholipid antibodies (221–224).
The elastic tissue may still appear normal in the early
stage of an erythematous lesion (225). Usually, however,
it is already decreased or even absent within the lesion
(235). In cases in which there is a decrease in the amount
of elastic tissue, mononuclear cells may be seen adhering
to elastic fibers (232). Elastophagocytosis within macrophages and giant cells may be seen (236).
Longstanding, noninflammatory lesions generally
show a more or less complete loss of elastic tissue, either
in the papillary and upper reticular dermis or in the upper
reticular dermis only (Fig. 15-9). A perivascular and
periadnexal lymphocytic infiltrate of varying intensity is
invariably present, so that a distinction of an inflammatory and a noninflammatory type is not justified. In some
instances, the involved areas show small, normal elastic
fibers, which are probably the result of resynthesis, or
abnormal, irregular, granular, twisted, fine fibers (188).
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A
B
Figure 15-9 Anetoderma. Decreased to absent elastic fibers in a case of anetoderma (A) as compared with a normal control (B).
Immunofluorescence studies of primary anetoderma have
revealed immune deposits in a pattern indistinguishable
from that of lupus erythematosus (237,238).
Pathogenesis. Electron microscopic examination of
lesions reveals a few thin, irregular elastic fibers, with more
or less complete loss of the amorphous substance elastin
but with relative conservation of the microfibrils. Macrophages, lymphocytes, and some plasma cells are observed.
It appears possible that partial destruction by elastases
originating in the macrophages occurs, because it is known
that the elastases preferentially destroy the amorphous substance of the elastic fibers (238). Two elastase-type, proteinases, gelatinase A (metalloproteinase 2) and B (MMP-9),
have been shown to have increased expression in skin
explants from patients with anetoderma (239). Morphometric analysis has demonstrated decreases in the diameter
of oxytalan and dermal elastic fibers as well as the volume
fractions of pre-elastic and dermal elastic fibers (240). This
analysis has been used to differentiate anetoderma from
other disorders of elastic tissue such as cutis laxa.
There is increasing evidence for an immunologic basis
for anetoderma. In support of this hypothesis is the association of numerous autoimmune disorders and the findings
of immune deposits at both the dermoepidermal junction
and dermal blood vessels (208,237). In particular, the
association of antiphospholipid antibodies with anetoderma is intriguing. The exact mechanism by which these
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antibodies may induce lesions remains to be elucidated.
Some authors have postulated microthrombosis produced
by antiphospholipid antibodies with resultant ischemia
of dermal tissues may induce elastic fiber degeneration
(212,215). Others have hypothesized that the antibodies
may alter the inhibitors of elastolytic enzymes, thus allowing the destruction of elastic fibers (241).
Principles of Management. Various modalities such as
aspirin, phenytoin, dapsone, vitamin E, colchicine, and
hydroxychloroquine have been tried, and may have some
short-term benefit, but the long-term outcomes have been
disappointing (155).
PERIFOLLICULAR ELASTOLYSIS
Clinical Summary. Perifollicular elastolysis is a relatively
common condition consisting of small, hypopigmented,
follicular papules on the face and upper trunk. The papules may protrude or herniate (242–245). There is a strong
association with acne vulgaris and some have suggested
the term papular acne scars for the disorder (245).
Histopathology. There is an absence of elastic fibers
localized to the regions around pilosebaceous units (242).
Pathogenesis. Perifollicular elastolysis most likely represents a form of anetoderma related to acne scarring (245).
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Elastase-producing strains of Staphylococcus epidermidis
have been found in lesional hair follicles and have been
proposed as the causative factor (242,244).
Principles of Management. There is no known treatment.
ACRO-OSTEOLYSIS
Clinical Summary. The term acro-osteolysis refers to
destructive lytic changes on the distal phalanges. Three
types are recognized: familial; idiopathic, nonfamilial; and
occupational, which is associated with exposure to vinyl
chloride gas. In addition, acro-osteolysis may be a feature
of genetic syndromes such as Haim–Munk syndrome,
pycnodysostosis, Hutchinson–Guilford syndrome, and
Hajdu–Cheney syndrome (246–249).
The familial type affects mainly the phalanges of the feet
and is associated with recurrent ulcers on the soles (250).
The idiopathic type affects the hands more severely
than the feet. Involvement of the distal phalanges of the
fingers causes shortening of the fingers. This variant
may be associated with Raynaud phenomenon. Only one
case has been described, with cutaneous lesions consisting of numerous yellow papules 2 to 4 mm in diameter
and showing a linear distribution and coalescence into
plaques, mainly on the arms (250).
Occupational acro-osteolysis, like the idiopathic type,
causes shortening of the fingers due to osteolysis. This
variant is often associated with Raynaud phenomenon and
progressive thickening of the skin of the hands and forearms simulating scleroderma. There may be erythema of
the hands, and the thickening may consist of papules and
plaques (251). The skin of the face may show diffuse induration (252). In addition, there may be thrombocytopenia, portal fibrosis, and impaired hepatic and pulmonary
function (253). A variant of occupational acro-osteolysis
has been described in guitar players and is believed to be
secondary to mechanical stress (254, 255).
Histopathology. The histologic changes in the papules
and plaques of idiopathic and occupational acro-osteolysis consist of thickening of the dermis, with swelling and
homogenization of the collagen bundles, indistinguishable from scleroderma. Staining for elastic tissue shows
disorganization of the elastic fibers, which appear thin and
fragmented (250–252).
Pathogenesis. Vinyl chloride disease is an immune-complex disorder associated with hyperimmunoglobulinemia,
cryoglobulinemia, and evidence of in vivo activation of
complement (253). The immunologic nature of the disease explains why it is developed by fewer than 3% of the
workers exposed to vinyl chloride gas (251).
Principles of Management. Other than treatment and supportive care of the underlying cause, when one is identified, there are no specific therapeutic options.
Elder9781451190373-ch015.indd 472
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