Chapter 71 :: Acquired Perforating Disorders :: Garrett T. Desman & Raymond L.

Barnhill
The perforating disorders are a group of conditions characterized by the transepidermal
elimination of connective tissue elements. Although this finding may be the primary
manifestation of familial or acquired systemic conditions (ie, chronic renal failure, diabetes
mellitus), the perforation of dermal elements also may be seen as a secondary component to
other primary dermatoses (eg, perforating granuloma annulare, gout, perforating
pseudoxanthoma elasticum) (Table 71-1). Rare familial primary perforating disorders typically
present in childhood and are characterized histopathologically by the transepidermal
elimination of collagen (reactive perforating collagenosis) or elastic fibers (elastosis perforans
serpiginosa). Similar adult-onset nonfamilial/acquired lesions are most commonly associated
with chronic kidney disease and diabetes mellitus. These cases were originally given various
appellations within the medical literature, complicating the subject matter (Table 71-2).
Eventually, comprehensive review of the literature concluded that 4 separate clinicopathologic
entities characterized the adult-onset acquired primary perforating disorders: Kyrle disease
(KD), acquired perforating collagenosis (APC), perforating folliculitis, and acquired elastosis
perforans serpiginosa (AEPS).1-4 Further studies, however, have reported more
clinicopathologic similarities
than differences among these acquired conditions, in particular, a varied composition of
extruded contents (ie, collagen, elastin fibers, fibrin) from lesion to lesion in the same patient.
This has resulted in some authors advocating for a combined designation of acquired
perforating dermatosis (APD).5,6 Although the use of this unified designation is encouraged, an
acknowledgment of the clinical and histopathologic manifestations of these 4 described
conditions is important for understanding the spectrum of findings as well as possible
correlations with systemic disease (Table 71-3).
CLINICAL FEATURES APD is an umbrella designation for adult-onset acquired perforating disease
encompassing KD, APC, perforating folliculitis, and AEPS, with AEPS exhibiting distinctive clinical
findings and disease associations. No geographic or clear racial predilection has been
established. APD is characterized clinically by round, umbilicated, skin-colored, erythematous or
hyperpigmented papules and nodules with a central crust or keratotic plug, predominantly
involving the extensor surfaces of the extremities and the trunk (APC, KD) (Fig. 71-1). Lesions
less commonly involve the face or scalp. Although the central keratotic core is the most specific
clinical finding, it is occasionally removed by the patient, leaving behind only a shallow crater.
Mucous membranes are spared. In rare cases, purple annular plaques or pustules mixed with
papules have been observed. Scratching of APD lesions can lead to koebnerization with linear
umbilicated papules arising in excoriated skin. Some lesions may exhibit a follicular-based
distribution with minimal Koebner response (perforating folliculitis; Fig. 71-2). Lesional pain and
pruritus, ranging from mild-tosevere and intractable, have been reported.6 Elastosis perforans
serpiginosa, whether familial or acquired, exhibits papules in a serpiginous configuration, often
with central atrophy, and typically is localized to 1 region of the body, such as the neck, trunk,
or the extremities (Fig. 71-3). These lesions are frequently asymptomatic and only occasionally
manifest a koebnerization response. Elastosis perforans serpiginosa affects nearly 4 times more
males than females. The familial form of the disease has a reported autosomal dominant mode
of inheritance.7 The term reactive perforating collagenosis refers to an extremely rare familial
disorder that most commonly presents in early childhood with an equal sex distribution. Both
autosomal dominant and recessive modes of inheritance have been reported. Similar to KD and
APC, following superficial trauma, small keratotic papules develop on the upper and lower
extremities,
ASSOCIATIONS OF ACQUIRED PERFORATING DISORDERS
The most common systemic conditions associated with adult-onset APD are chronic kidney
disease (CKD) and diabetes mellitus (DM). APD has been documented in 4.5% to 10% of
hemodialysis patients in North America and in 11% of a dialysis population (both hemodialysis
and peritoneal dialysis) in Great Britain.9,10 Not surprisingly, the most common cause of CKD
among APD patients is diabetic nephropathy.10 APD also has occurred in patients with chronic
renal dysfunction who are not undergoing dialysis, as well as in those patients who have
received renal transplants.
Interestingly, in a series of 22 patients with APD, 3 were healthy with no known associated
illnesses.6 Some advocate that the phenomenon of APD simply represents a form of prurigo
nodularis owing to its association with other pruritic conditions, such as insect bites and
scabies, lymphoma, and hepatobiliary diseases.11-18 Lesions associated with CKD and DM
typically follow a chronic course that parallels systemic disease (KD, acquired reactive
perforating collagenosis). Follicular-based lesions unassociated with CKD or DM typically lack a
Koebner response and may follow a waxing-and-waning course. APD has rarely been associated
with the use of certain therapeutics, including tumor necrosis factor-α inhibitors, indinavir, and
sorafenib.19-22 AEPS is well recognized as a potential adverse effect of prolonged D-
penicillamine therapy.22 As mentioned earlier in this section, some elastosis perforans
serpiginosa cases are familial and associated with an autosomal dominant mode of inheritance.
Other associations include Down syndrome and various inborn disorders of connective tissue
metabolism, such as Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta,
scleroderma, and pseudoxanthoma elasticum. However, rare cases of AEPS have been reported
in patients with CKD in the absence of penicillamine exposure or other known associations.1
Table 71-3 lists less-commonly reported associations with APD.
ETIOLOGY AND PATHOGENESIS
Although the precise etiology and pathogenesis of APD are unknown, a complex interaction
between epithelium, connective tissue, and inflammatory mediators is most likely involved.
According to the current trend for unification, perforating folliculitis and APC may be
phenotypic variants of a disease spectrum or merely different stages in lesional development.
KD most likely represents an extreme phenotype or end-stage manifestation of the 2 former
conditions. Controversy still exists regarding whether perforating folliculitis represents a true
primary perforating disease as ruptured follicles with extruded stromal elements are a feature
of many infectious conditions, such as Pityrosporum folliculitis. Regardless, as APD is most
strongly associated with pruritic conditions, superficial trauma to the epidermis most likely
represents the primary inciting factor in susceptible patients. This is highlighted by the fact that
many patients have common prurigo nodules in addition to classic perforating lesions.
Additionally, resolution of APD lesions with discontinuation of manipulation/trauma supports
this mechanism.6 Predisposing conditions include vasculopathy/angiopathy (related to DM),
microdeposition of exogenous materials within the dermis (including calcium salts and silicon,
pertinent to the increased frequency of APD in dialysis patients), and epidermal or dermal
change related to metabolic derangements including vitamin A deficiency.
A recent study indicates a role of advanced glycation end product–modified collagens I and III,
where traumatized keratinocytes bind to these extracellular matrix proteins via advanced
glycation end product receptor CD36, inducing keratinocyte terminal differentiation and
upward movement of keratinocytes along with glycated collagen.27 Fibronectin also has been
implicated because it links keratinocytes with Type IV collagen within the basement membrane
and plays a vital role in epithelial cell signaling, migration, and differentiation. Increased
fibronectin levels have been documented in the serum of patients with DM and uremia, as well
as within the skin at sites of transepidermal elimination.28 Imbalances in transforming growth
factor-β3, matrix metalloproteinase-1, and tissue inhibitor of metalloproteinase-1 also have
been demonstrated in APD lesions; whether these alterations are pathogenic or reflective of
normal wound healing is currently unknown.26,29 Whether the pathogenesis of the familial
primary perforating dermatoses is different from the acquired forms is also unknown.
Transepidermal elimination of Type IV collagen has been documented in both familial reactive
perforating collagenosis and APC.30 In elastosis perforans serpiginosa, enhanced expression of
elastin receptors has been detected in the epidermis surrounding the elastic material in both
familial and acquired conditions.31 However, in penicillamine-associated AEPS, it is
hypothesized that penicillamine alters dermal elastic fibers in affected patients.32 Elastic fiber
abnormalities, including “bramble bush–appearing” fibers of variable thickness and increased
numbers of fibers in the papillary and reticular dermis, have been described in patients with
penicillamine-induced AEPS.
DIAGNOSIS HISTOPATHOLOGY
The diagnosis of APD is based on clinical and histopathologic findings. Folliculitis and prurigo
nodularis may occur concomitantly, especially in patients with CKD, therefore multiple biopsies
should be taken if lesions show different clinical morphologies. APD is characterized
histologically by transepidermal elimination of dermal material through an epidermal
invagination, which may be follicular or perifollicular. Lesions typically demonstrate a central
keratotic plug with crusting or hyperkeratosis; parakeratosis is variable. Within the dermis
surrounding the perforation, there is often a focal inflammatory infiltrate with neutrophils
predominating in early lesions and lymphocytes, macrophages, or multinucleated giant cells
present in older lesions. The 4 initially identified acquired perforating disorders (APC, AEPS, KD,
and perforating folliculitis) were classically differentiated histopathologically on the basis of the
nature of the eliminated dermal material. In APC, collagen bundles are detected within the plug
(Fig. 71-4); in AEPS, elastic fibers are instead noted (Fig. 71-5). In KD, amorphous dermal
material with fibrin and/or keratin comprises the extruded contents. Perforating folliculitis is
characterized by perforation of the follicular epithelium by degenerating collagen and
extracellular matrix.
Clear identification of the eliminated material may be impossible and, in addition, multiple
substances (ie, collagen and elastic fibers) may be simultaneously detected, reinforcing the
clinical and histopathologic overlap within APD.5,6 Lesions of familial reactive perforating
collagenosis and elastosis perforans serpiginosa characteristically contain extruded collagen
and elastin, respectively.
LABORATORY TESTS
Laboratory evaluation for comorbidities should include fasting blood glucose; glucose tolerance
test; serum creatinine; glomerular filtration rate or creatinine clearance; serum uric acid; liver
function tests; and thyroid function tests. A comprehensive family and past medical history, as
well as review of systems, should be obtained. Additional diagnostic testing for associated
conditions (Table 71-4) should be performed as indicated. DIFFERENTIAL DIAGNOSIS The
differential diagnosis of APD is broad and includes infectious, inflammatory, and neoplastic
disorders, including those that koebnerize (Table 71-5). APD can be especially difficult to
differentiate from prurigo nodularis. Perforating pseudoxanthoma elasticum should be
distinguished from AEPS.
CLINICAL COURSE, PROGNOSIS, AND MANAGEMENT COMPLICATIONS
Most complications that occur in patients with APD arise from underlying systemic illnesses.
However, patients should be monitored for secondary infection (bacterial, fungal, and viral) as
well as parasitic infestation. In an attempt to relieve the associated pruritus, patients may apply
products to their skin that may result in irritant or allergic contact dermatitis. In darker-skinned
patients with more excoriations, postinflammatory pigmentary alteration and scarring can be
significant.
PROGNOSIS
The prognosis of APD is heavily linked to the presence of underlying diseases. Some studies
have shown that APD may improve with successful treatment of the underlying illness.34 Most
cases of APD continue for years unless treated.
MANAGEMENT
Treatment of APD is difficult. Table 71-6 details the therapeutic options that are described in
the literature to date. There have not been any well-designed clinical trials of treatment for
APD, and current treatment strategies are based largely on anecdotal reports. In patients with
CKD, improvement in APD lesions has been reported after changing the type of dialysis tubing
or modification of the dialysis procedure.10 In a few cases, APD has resolved following renal
transplantation.9,35,36 The most commonly employed treatments for APD include topical and
oral retinoids, topical and intradermal corticosteroids, and ultraviolet B phototherapy.
Phototherapy is effective for uremic pruritus and therefore may be particularly beneficial for
patients with CKD by reducing koebnerization.37 Several authors have reported improvement
in APD following treatment with allopurinol in cases of elevated or normal uric acid levels.37
Currently available therapeutic options may not provide complete resolution of APD lesions or
associated symptoms.