Perforating dermatoses

INTRODUCTION — The perforating dermatoses represent a group of skin disorders characterized by the "perforation," or elimination, of dermal connective tissue through the epidermis. Although several classifications exist, there are four major "primary" perforating disorders grouped according to the types of epidermal disruption, nature of eliminated material, and clinical features [1]:

●Reactive perforating collagenosis (RPC) (picture 1A)

●Elastosis perforans serpiginosa (EPS) (picture 2A-B)

●Perforating folliculitis (PF) (picture 3A-B)

●Acquired perforating dermatosis (APD; which encompasses Kyrle disease, acquired RPC, acquired PF, and acquired EPS and is often associated with underlying chronic renal failure or diabetes mellitus (picture 4A-B and table 1)

Of note, cases of clinical and histologic overlap among the perforating diseases have been reported, and diagnostic criteria are not well defined for each entity. Additionally, there are "secondary" perforating diseases in which transepidermal elimination occurs only as part of the underlying primary dermatosis. These disorders often involve elimination of endogenous material, foreign material, infectious organisms, granulomatous material, or neoplastic cells (table 2).

The epidemiology, pathogenesis, clinical manifestations, diagnosis, and management of the primary perforating dermatoses will be reviewed here.

REACTIVE PERFORATING COLLAGENOSIS — First described in 1967, reactive perforating collagenosis (RPC, MIM #216700) is a rare genetic disorder that usually begins in childhood [2,3]. Fewer than 50 cases have been reported in the literature. The mode of inheritance is unclear since autosomal dominant, autosomal recessive, and sporadic cases have each been reported. Acquired RPC is a manifestation of acquired perforating dermatosis (APD) and considered separate from RPC. (See 'Acquired perforating dermatosis' below.)

Pathogenesis — The pathogenesis of RPC is unknown. No specific genetic defect has been identified. An abnormal response to superficial trauma may contribute to lesion development. Experimental production of the classic RPC lesion has been reported with a needle scratch [4].

Clinical manifestations — Patients with RPC develop small keratotic papules that arise after superficial trauma. These grow within weeks to larger, umbilicated papulonodules, usually on the arms and hands, although they can develop anywhere on the body (picture 1A). RPC may koebnerize (occur in sites of skin trauma), commonly resulting in a linear configuration of nodules (picture 1B). Mucosal involvement is rare [5].

Lesions often present in multiple stages of development and regression and vary from several to more than 30 in an individual patient [2]. The papulonodules may resolve over six to eight weeks with resultant scarring and/or postinflammatory hyperpigmentation [6].

Pathology — As with other perforating diseases, the histology depends on the stage of the lesion. New papulonodules display epidermal hyperplasia and degenerated basophilic collagen fibers. Later lesions demonstrate an invagination of the epidermis with a keratin plug. Vertically oriented basophilic collagen fibers are frequently seen with focal extrusions through the epidermis, highlighted with Verhoeff-Van Gieson staining, which stains the collagen fibers red. Typically, no staining of elastic fibers should be seen, in contrast to elastosis perforans serpiginosa (EPS). An associated perivascular lymphohistiocytic infiltrate may be present [7].

Diagnosis — A diagnosis of RPC is made based upon the recognition of consistent histologic findings (collagen within a keratin plug or extruding through the epidermis), consistent clinical features (keratotic papules or umbilicated papulonodules), an early age of onset, and the absence of a disease associated with APD. A punch biopsy typically provides a sufficient specimen for histopathologic examination. (See 'Acquired perforating dermatosis' below.)

A positive family history provides additional support for this diagnosis. There is no genetic test for RPC.

Differential diagnosis — The differential diagnosis is similar for many of the perforating disorders. The physical and histologic findings, childhood onset, and family history help distinguish RPC from the following entities:

●Folliculitis – Folliculitis can usually be differentiated by the appearance of pustules, some with a central hair protruding, or erythematous, inflamed papules in a hair-bearing site (picture 5). A biopsy would demonstrate inflammatory cells in the follicular wall and ostia. (See "Infectious folliculitis".)

●Arthropod bites – Although clinically similar to RPC, arthropod bites often lack an umbilicated center and histologically reveal a predominately eosinophilic infiltrate. (See "Insect and other arthropod bites".)

●Prurigo nodularis – Prurigo nodularis may clinically resemble RPC; however, the lesions of prurigo nodularis are usually more nodular and histologically show compact hyperkeratosis, irregular acanthosis, and a perivascular inflammatory infiltrate with thickened dermal collagen (picture 6). (See "Prurigo nodularis".)

●Multiple keratoacanthoma – Clinically, keratoacanthomas are more crater like than RPC and filled with a keratinaceous crust (picture 7). Histologically, they demonstrate a central core of keratin and mild pleomorphism with a well-differentiated squamous epithelium. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Multiple keratoacanthomas'.)

●Dermatofibroma – Dermatofibromas usually occur as solitary, firm, flesh-colored nodules, commonly on the lower extremities (picture 8). On histology, dermatofibromas show a dermal spindle cell proliferation with trapped collagen. (See "Overview of benign lesions of the skin", section on 'Dermatofibroma'.)

Treatment — Most patients with RPC have mild disease that is rarely problematic and spontaneously resolves. Simple observation and avoidance of trauma, while waiting for lesions to involute, is the mainstay of management.

In select cases with widespread involvement or severe symptoms, treatment may be indicated. No randomized controlled trials have evaluated treatments for RPC, and the following treatments are based solely on data from case reports and case series. Improvement has been demonstrated with topical corticosteroids, intralesional corticosteroids, and topical retinoids [8,9]. Methotrexate has been reported to reduce the development of new lesions over a 10-month period at doses of 25 to 35 mg weekly [4]. Treatment failures have been documented with oral vitamin A, prednisone, oral antibiotics, and topical keratolytics [7].

The management of RPC that occurs as a manifestation of APD is reviewed separately. (See 'Acquired perforating dermatosis' below.)

Prognosis — The disease often persists into adulthood and may cause some residual scarring.

ELASTOSIS PERFORANS SERPIGINOSA — First described in 1953 as keratosis follicularis perforans, elastosis perforans serpiginosa (EPS) is a rare disorder that begins in early childhood or young adulthood and exhibits transepidermal elimination of abnormal elastic fibers [10]. Approximately 25 to 40 percent of cases of EPS occur in association with genetic diseases such as Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, pseudoxanthoma elasticum, acrogeria, Rothmund-Thomson syndrome, and osteogenesis imperfecta. Alternatively, EPS can be familial [11,12]. Approximately 75 percent of affected patients are male [13].

A drug-induced form of EPS also exists (see 'Pathogenesis' below). Rarely, EPS occurs as a manifestation of acquired perforating dermatosis (APD). (See 'Acquired perforating dermatosis' below.)

Pathogenesis — Although some authors theorize that focal irritation in the dermis may cause the formation of the epidermal and follicular channels that extrude the irritating agent, the pathogenesis of EPS remains unknown.

Drug-induced EPS most often occurs in relation to D-penicillamine use, which disturbs desmosine crosslinks within elastin. D-penicillamine-induced EPS generally develops several years after drug initiation. Although D-penicillamine has been used to treat Wilson disease, cystinuria, and rheumatoid arthritis, EPS has primarily been reported in patients treated for Wilson disease, probably because these patients require high drug levels over many years [14].

Clinical manifestations — EPS presents as skin-colored to slightly erythematous, keratotic, small papules arranged in an annular or serpiginous pattern (picture 2A-B). EPS often develops on the lateral neck and occasionally occurs on the face, arms, or flexural areas. Lesions may have central scaling, atrophy, or hypopigmentation and can be arranged symmetrically with satellite lesions. While generally asymptomatic, EPS is sometimes pruritic. As with other perforating disorders, papules and plaques in different stages of development are often visible.

Pathology — Histologically, EPS displays a narrow, transepidermal or perifollicular canal extending in a straight or corkscrew pattern from the dermis. There is a mixture of degenerated, eosinophilic elastic fibers, basophilic debris, and mixed inflammatory cells with lymphocytes, macrophages, or multinucleated giant cells [12,13]. A notable increase in the thickness and amount of papillary dermal elastic tissue can be visible. The epidermis may be acanthotic and hyperkeratotic. Verhoeff-Van Gieson staining of elastic fibers can highlight the distinctive changes of EPS (picture 9).

Characteristically, light and electron microscopy of D-penicillamine-induced EPS display a "bramble-bush" or "lumpy-bumpy" appearance of the elastic fibers, with elastic tissue changes occurring in lesional and nonlesional skin, differentiating it from other forms of EPS (picture 10A-B) [13,15].

Diagnosis — The diagnosis of EPS is based on the recognition of the classic histopathologic findings of transepidermal elimination of elastic fibers in the context of annular or serpiginous, keratotic papules. A punch biopsy of a representative lesion is appropriate to confirm the diagnosis. Adult-onset EPS that occurs in the setting of systemic disease, such as renal failure or diabetes mellitus (table 1), is considered a manifestation of APD. (See 'Acquired perforating dermatosis' below.)

Differential diagnosis — EPS may resemble other annular or serpiginous dermatoses including:

●Tinea corporis – Appearing as annular, scaly plaques with central clearing, tinea corporis will demonstrate branching hyphae on potassium hydroxide examination performed on a skin scraping, confirming the diagnosis of dermatophytosis (picture 11). (See "Dermatophyte (tinea) infections", section on 'Tinea corporis'.)

●Granuloma annulare – Similar to EPS, granuloma annulare can present with annular, erythematous plaques (picture 12). However, granuloma annulare generally lacks any associated scale and on biopsy reveals palisading granulomas. (See "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis".)

●Sarcoidosis – Sarcoidosis can present with annular and arcuate erythematous plaques (picture 13). Biopsy, however, will reveal non-necrotizing granulomas. (See "Cutaneous manifestations of sarcoidosis".)

●Porokeratosis of Mibelli – Porokeratosis of Mibelli presents as slightly atrophic plaques with ridge-like, hyperkeratotic, slightly scaly, erythematous borders that may resemble EPS (picture 14). Biopsy will differentiate the entities; porokeratosis has a classic cornoid lamella, a thin column of closely packed parakeratotic cells in a keratin-filled epidermal invagination not seen in EPS. (See "Porokeratosis", section on 'Porokeratosis of Mibelli'.)

●Discoid lupus erythematosus (DLE) – DLE usually appears as plaques with variable hyperkeratosis and hypo- or hyperpigmentation (picture 15). Lesions are usually chronic in nature and are often found in sun-exposed areas. A biopsy will help distinguish DLE from EPS; superficial and deep perivascular and periadnexal lymphocytic infiltrates are seen in DLE. (See "Overview of cutaneous lupus erythematosus", section on 'Discoid lupus erythematosus'.)

Treatment — Treatment of EPS is not required but may be employed to improve the appearance of affected skin or associated symptoms. A variety of topical medical and destructive treatments have been used; however, no randomized clinical trials exist, and published treatment recommendations are based on case reports. Also, the potential for spontaneous resolution makes it difficult to adequately interpret therapeutic efficacy.

Common well-tolerated initial treatments for small areas of EPS include moderate-potency topical corticosteroids, topical retinoids [16], cellophane tape stripping (to remove keratinous material) [11,12], cryosurgery [17], and electrodesiccation and curettage [18]. Successful treatment of D-penicillamine-induced EPS with a fractional carbon dioxide laser has been reported [19]. EPS has also been treated with other lasers, including pulsed dye lasers and erbium:yttrium aluminum garnet (Er:YAG) lasers [20-22]. Reported therapies with little to no sustained success include calcipotriene [18], glycolic or salicylic acid, and narrowband ultraviolet B phototherapy [18].

Prognosis — EPS can persist for several years before spontaneously resolving but has a tendency to recur. The course of individual EPS lesions in a single patient can vary. D-penicillamine-induced EPS often resolves after withdrawal of the medication.

PERFORATING FOLLICULITIS — Perforating folliculitis (PF) was first described in 1968 as a uniform eruption with discrete, keratotic, follicular-based papules primarily on the extremities [23]. Whether PF exists as a separate, definable perforating disorder, or is a feature of a wide variety of cutaneous diseases where follicular perforation or disruption occurs, is controversial. Classically (and in the authors' opinion), PF is its own entity. PF occurring in the setting of underlying systemic disease, such as chronic renal failure or diabetes mellitus, is an exception. Such cases may be considered a manifestation of acquired perforating dermatosis (APD) (table 1). (See 'Acquired perforating dermatosis' below.)

Relatively uncommon, PF occurs in patients ranging in age from 6 to 72 years, affecting males and females equally [7]. Several cases of PF have been associated with psoriasis [24].

Pathogenesis — Although the pathogenesis of PF is unknown, several authors have postulated that chronic friction or irritation incites abnormal keratinization within the follicular infundibulum, leading to epithelial perforation and exposure of the dermis to the follicular contents [7]. Other clinicians have theorized that mechanical disruption of the follicular epithelium by an entrapped hair may be causative, as trapped hairs may be seen on cross sectioning of some specimens. Further research is needed to clarify the causative factors.

Clinical manifestations — PF presents as discrete, erythematous, follicular-based papules with small, central, keratinous cores or central hairs (picture 3A-B). Disruption and removal of the hard, keratinaceous central plug can leave behind a bleeding, crater-like papule. PF is generally asymptomatic, favors the extremities and buttocks, and typically lasts months to years with periods of spontaneous remission and reoccurrence [7,23].

Pathology — Biopsy reveals a dilated follicular infundibulum with necrotic debris, orthokeratotic and parakeratotic keratin, and degenerated inflammatory cells. The underlying dermis may have degenerative changes with eosinophilic elastic fibers and collagen entering the perforation; a curled-up hair is a frequent, but not a necessary, finding [7,23].

Diagnosis — The diagnosis of PF is based upon the recognition of follicular-based papules demonstrating a dilated follicular infundibulum with necrotic debris, orthokeratotic and parakeratotic keratin, and degenerated inflammatory cells on histopathologic examination. Complete removal of a papule with a small punch biopsy is recommended since histologic findings are focal and can be missed if the biopsy specimen is partial or incompletely sectioned.

Differential diagnosis — Examples of disorders in the differential diagnosis of PF include:

●Keratosis pilaris (KP) – KP consists of small, skin-colored, keratotic follicular papules typically on the upper arms and thighs (picture 16). KP papules are smaller and more closely grouped than PF. Histologically, KP demonstrates conical follicular dilation with orthokeratotic keratinaceous material but has neither follicular disruption nor an inflammatory cell infiltrate. (See "Keratosis pilaris".)

●Bacterial folliculitis – Bacterial folliculitis represents a bacterial infection of the hair follicle, often presenting as a folliculocentric pustule (picture 5). While PF can appear to have a central pustule, the central plug of PF is not composed of purulent material but rather keratinaceous material. On biopsy, PF also has no acute follicular inflammation, as demonstrated in bacterial folliculitis. If bacterial colonies are histologically present in PF, they are located only in the superficial portion of the hair follicle, in contrast to bacterial folliculitis, where the bacteria may be observed deep in the hair follicle as well. (See "Infectious folliculitis".)

●Acne vulgaris – Acne vulgaris generally develops on the face, chest, and/or back of teenagers and young adults. In contrast, PF can arise in all decades of life and occurs primarily on the hair-bearing areas of the extensor surfaces. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris".)

Treatment — Treatment of PF is challenging. No randomized trials have been performed, and there is no clear effective treatment. Topical retinoid therapy appeared beneficial in a case report [24]. Oral apremilast therapy appeared beneficial in a patient with PF/elastosis perforans serpiginosa (EPS) overlap in the setting of psoriasis and Down syndrome [25]. However, poor responses to systemic antibiotics, oral vitamin A, topical keratolytics, and topical corticosteroids have been reported [7,23]. The management of PF that occurs as a manifestation of APD is reviewed separately. (See 'Acquired perforating dermatosis' below.)

Prognosis — PF generally lasts from months to years, undergoing periods of remissions and relapses.

ACQUIRED PERFORATING DERMATOSIS — Acquired perforating dermatosis (APD) is an all-encompassing term that describes the various types of perforating diseases that arise in adults, often related to an underlying systemic disease, most commonly diabetes mellitus and chronic renal failure [26,27]. APD encompasses acquired reactive perforating collagenosis (RPC), acquired elastosis perforans serpiginosa (EPS), acquired perforating folliculitis (PF), and the classically described Kyrle disease, though among authors the classification is debated [1]. Acquired RPC is the most common form of APD, with acquired PF, Kyrle disease, and EPS observed less frequently.

Kyrle disease was first described in 1916 as hyperkeratosis follicularis et parafollicularis in cutem penetrans [28]. It was initially thought to have a genetic basis, but most reports since then have linked it to diabetes mellitus or chronic kidney disease [29]. Given the similar epidemiologic, clinical, and pathologic factors observed, Kyrle disease is most accurately considered as part of APD.

APD occurs primarily in middle-aged adults and in association with an underlying systemic disease (table 1). It is most common in patients with diabetes and patients with chronic renal failure on hemodialysis. APD occurs in up to 11 percent of patients receiving hemodialysis [30].

Pathogenesis — The pathogenesis is unknown, and controversy surrounds whether the defect is epidermal or dermal. Further research is needed to clarify the factors and mechanisms involved. Several hypotheses exist:

●Chronic rubbing from the pruritus of the underlying disease may result in epithelial hyperplasia, the elimination of dermal material, and abnormal keratinization [31,32].

●An infectious etiology may be causative, based on case reports where lesions resolved with antimicrobial therapy [33].

●Reduced blood supply secondary to microangiopathy may be a culprit, leading to focal necrobiosis of tissue; however, histologic data do not support this theory [31].

●Overexpression of transforming growth factor-3 has been demonstrated around the epidermal depression in lesions of APD. This factor plays a role in wound healing and connective tissue remodeling. Matrix metalloproteinases have also been found to be increased in tissue of APD, suggesting these factors may help regulate epidermal hemostasis and alter extracellular matrix protein remodeling [34,35].

●Defective differentiation of the epidermis and dermal-epidermal junction may occur secondary to alteration of glycosylation, as seen in diabetes mellitus [36].

●Elevated serum and tissue fibronectin may stimulate the epithelial proliferation and epidermal perforation found in APD [37].

Although many diseases have been linked with APD, chronic renal failure and diabetes are by far the most frequent associations (table 1). In patients with chronic renal failure, APD most commonly arises after the initiation of dialysis and almost always resolves after renal transplantation [38].

Additional cases of APD described as acquired PF or acquired RPC have arisen after the administration of several classes of drugs (table 3). D-penicillamine-related EPS is commonly considered a subtype of EPS and not as an APD. (See 'Elastosis perforans serpiginosa' above.)

Clinical manifestations — APD appears as 2 to 10 mm umbilicated, hyperkeratotic papules, some with a central, white, keratotic crust (picture 4A-B). Koebnerization may occur, and chronic rubbing and scratching of pruritic areas may cause the papules to coalesce into larger plaques (picture 17). A giant variant of APD has been reported where one plaque reached nearly 2 cm in diameter [39].

APD papules often develop on the extensor surfaces of the extremities, though reports also detail involvement of the trunk, scalp, conjunctiva, and buccal mucosa [40]. Pruritus is nearly uniform. Pain may occur but is rare [41]. Infrequently, lesions may be secondarily infected with bacteria, fungi, or atypical mycobacteria.

Pathology — The histologic features of APD may be consistent with any of the classical perforating diseases, including RPC, PF, Kyrle disease, and, less commonly, EPS [41]. Biopsy reveals a cup-shaped invagination with a keratotic plug penetrating the papillary dermis with underlying dermal lymphocytic and histiocytic infiltrate. Orthokeratosis, parakeratosis, and abnormal keratinization may be evident. Transepidermal elimination of collagen, elastic fibers, and degenerated follicular material with or without collagen and elastin may be visualized, as seen in classic RPC, EPS, and PF, respectively. Often, basophilic debris is found in the keratotic plug (picture 18A-B). Alternatively, transepidermal elimination of keratotic material may be observed, as in classically described Kyrle disease [42].

Diagnosis — The diagnosis of APD is based on characteristic clinical findings of umbilicated, hyperkeratotic papules with histopathology demonstrating transepidermal elimination of elastin, collagen, or follicular material. These pathologic findings overlap with classic RPC, PF, and EPS. An association with systemic disease, particularly chronic renal failure or diabetes mellitus, distinguishes APD (table 1).

Common dermoscopic features of APD may include the following: a central, keratotic plug (angulated or rounded) that appears yellow or homogeneous in the center of the lesion; a white, homogenous area around the plug ("white collar sign"); dotted and linear vessels distributed radially; and an outer zone of hyperpigmentation [43,44].

Laboratory studies may reveal elevated blood glucose or elevated hemoglobin A1C, indicating underlying diabetes mellitus. Liver or renal function studies may also point to underlying organ dysfunction. The history, review of systems, and physical examination should guide other laboratory or imaging work-up for an associated disease or neoplasm.

Differential diagnosis — Several entities may appear similar to APD, especially those with multiple, umbilicated nodules:

●Folliculitis – Folliculitis can usually be differentiated by the presence of pustules, some with a central hair protruding, or erythematous, inflamed papules in a hair-bearing site (picture 5). A biopsy demonstrates inflammatory cells in the follicular wall and ostia. (See "Infectious folliculitis".)

●Arthropod bites – Although clinically similar to RPC, arthropod bites often lack an umbilicated center and histologically reveal a predominately eosinophilic infiltrate. (See "Insect and other arthropod bites".)

●Prurigo nodularis – Prurigo nodularis may clinically resemble RPC; however, the lesions of prurigo nodularis are usually more nodular and histologically show compact hyperkeratosis, irregular acanthosis, and a perivascular inflammatory infiltrate with thickened dermal collagen (picture 6). Notably, patients with APD can also suffer from prurigo nodularis, given that pruritus may predispose patients to both conditions. (See "Prurigo nodularis".)

●Multiple keratoacanthoma – Clinically, keratoacanthomas are more crater like and filled with a keratinaceous crust (picture 7). Histologically, they demonstrate a central core of keratin and only mild pleomorphism and well-differentiated squamous epithelium. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Multiple keratoacanthomas'.)

●Dermatofibroma – Dermatofibromas usually occur as solitary, firm, flesh-colored nodules commonly on the lower extremities (picture 8). They display characteristic histology of a dermal spindle cell proliferation with trapped collagen. (See "Overview of benign lesions of the skin", section on 'Dermatofibroma'.)

●Lichen planus – Especially if lesions koebnerize, lichen planus may be mistaken for a perforating disorder. While having a hyperkeratotic surface, lichen planus rarely demonstrates a central necrotic core (picture 19). Biopsy would reveal basal layer degeneration and a band-like lymphocytic infiltrate along the dermal-epidermal junction. (See "Lichen planus".)

●Darier disease – A genodermatosis, Darier disease or keratosis follicularis presents as greasy, hyperkeratotic papules coalescing into plaques in a seborrheic distribution (picture 20). Darier disease has associated mucous membrane and nail abnormalities not seen in APD. (See "Darier disease".)

●Verrucae vulgaris – Verrucae vulgaris appear as circumscribed, hyperkeratotic, rough papules, often on the hands, feet, or knees. Biopsy will differentiate verrucae vulgaris from APD by showing an acanthotic epidermis with hyperkeratosis and papillomatosis along with elongated rete ridges and thrombosed capillaries in the dermis. (See "Cutaneous warts (common, plantar, and flat warts)".)

●Atypical fungal or mycobacterial infection – Although these infectious entities may appear as hyperkeratotic nodules (often in a sporotrichoid or linear pattern) mimicking APD, biopsy will reveal granulomatous inflammation in the dermis and positive tissue staining or cultures.

Treatment — As with the prototypical perforating disorders, treatment for APD can be challenging. Therapies for APD have not been evaluated in randomized trials, and treatment measures are primarily based upon case reports or case series [45,46].

Our initial approach to APD is as follows:

●Treatment of underlying systemic disease. This may lead to improvement of APD.

●Antipruritic therapy with oral antihistamines and camphor- or menthol-based lotions. This should be combined with good bathing practices, including short baths or showers with lukewarm water, a mild cleanser or soap applied mainly to the body folds, and patting the skin dry with a towel. Within several minutes, an emollient cream or ointment should liberally be applied to the entire skin surface.

●Topical corticosteroids (group 2 to 3 (table 4)) applied twice daily for four to six weeks and/or intralesional corticosteroid injections (given every four to six weeks) to the most pruritic papules. Corticosteroids may help to alleviate pruritus through anti-inflammatory effects. Potential adverse effects include cutaneous atrophy and skin hypopigmentation.

●Topical keratolytics (eg, 5 to 7% salicylic acid) or topical retinoids applied to the more hyperkeratotic papules. Topical keratolytics reduce hyperkeratosis and improve the appearance of APD. A trial of salicylic acid involves daily application under occlusion for four to six weeks.

Retinoids, such as tretinoin 0.1% cream, can be applied nightly to affected areas to improve hyperkeratosis [47]. Skin irritation is a potential side effect of topical keratolytics and topical retinoids.

Patients with certain clinical features may benefit from additional measures:

●Individual symptomatic papules – Although not a viable option for the treatment of numerous sites, electrodessication and curettage can be used to remove individual symptomatic papules. Cryotherapy and cantharidin are alternative destructive treatments [45].

●Secondary bacterial infection – Oral antibiotics can be given if there is secondary bacterial infection.

●Widespread pruritic APD or insufficient symptomatic improvement from topical or intralesional therapy – APD may respond to ultraviolet B (UVB) phototherapy. In a case series of five patients, narrowband UVB therapy administered two to three times per week was associated with reduced pruritus and resolution of papules and nodules within 10 to 15 treatments [48]. Clearance persisted in two patients even after phototherapy was discontinued. The mechanism for phototherapy-induced improvement is unclear. Potential adverse effects include skin blistering, sunburn, and photoaging. (See "UVB phototherapy (broadband and narrowband)".)

●Refractory disease – Isotretinoin or allopurinol may be beneficial for refractory APD. In a case report, a 13-week course of oral isotretinoin (beginning with 1 mg/kg per day followed by a dose reduction), was associated with complete resolution of the skin manifestations of APD [45,49]. Benefit of isotretinoin for APD may be related to inhibition of abnormal keratinization, though this remains speculative. Isotretinoin is teratogenic. In the United States, participation in a Risk Evaluation and Mitigation Strategy risk management program is required for prescribing isotretinoin. Side effects of isotretinoin are reviewed in detail separately.

Allopurinol at doses of 100 mg daily for at least two months has ameliorated APD in some patients; however, other patients had recurrences despite continued therapy [39,50,51]. Allopurinol may improve APD by blocking collagen cross-linking or by inhibiting xanthine-oxidase, causing a reduction of oxygen free radicals, which may damage collagen. Adverse effects of allopurinol include gastrointestinal upset, severe skin rashes, and loss of appetite.

Other interventions for refractory disease that have seemed effective in individual patients include methotrexate [4,47], hydroxychloroquine [52], large doses of aqueous vitamin A (100,000 units per day for at least one month) [29], oral doxycycline or oral clindamycin given in the absence of known infection [33,53], and oral colchicine [54,55]. Oral dapsone and oral amitriptyline have also appeared effective in case reports [56,57]. In addition, transcutaneous electrical nerve stimulation resulted in complete clearance of APD in two patients with refractory disease [58]. Improvement in cutaneous lesions and associated pruritus has been reported in a patient treated with intranasal butorphanol, a drug with kappa-opioid receptor agonist and mu-opioid receptor antagonist activity [59].

Prognosis — The prognosis for APD is generally optimistic. Some patients note improvement in pruritus and diminishing of the skin lesions with treatment of the underlying systemic disease. Many patients, however, may experience a recurrence once treatment is withdrawn.

Follow-up — No specific follow-up is required; however, patients should be managed by an interdisciplinary team to treat associated systemic disorders.

SUMMARY AND RECOMMENDATIONS

●Overview – Perforating dermatoses are an uncommon group of papulonodular disorders with perforation or elimination of dermal connective tissue through the epidermis.

There are four major primary perforating dermatoses: reactive perforating collagenosis (RPC) (picture 1A-B), elastosis perforans serpiginosa (EPS) (picture 2A-B), perforating folliculitis (PF) (picture 3A-B), and acquired perforating dermatosis (APD) (picture 4A-B). (See 'Introduction' above.)

●Pathogenesis – The pathogenesis of perforating dermatoses is poorly understood; some diseases appear to have a genetic influence and erupt in childhood, such as RPC or EPS. APD, alternatively, does not seem to have a genetic basis but rather is observed in the setting of an underlying systemic disorder, especially chronic renal failure requiring dialysis or diabetes mellitus (table 1). (See 'Reactive perforating collagenosis' above and 'Elastosis perforans serpiginosa' above and 'Perforating folliculitis' above and 'Acquired perforating dermatosis' above.)

●Diagnosis – The diagnosis of perforating dermatoses is usually made through clinical examination and a skin biopsy demonstrating collagen or elastin perforation through the epidermis. No other laboratory studies are necessary for making the diagnosis; however, laboratory studies are indicated in cases of APD to look for an underlying systemic disease, if not already diagnosed. (See 'Reactive perforating collagenosis' above and 'Elastosis perforans serpiginosa' above and 'Perforating folliculitis' above and 'Acquired perforating dermatosis' above.)

●General management – The response to treatment of perforating dermatoses is variable. Most patients, especially with RPC or EPS, require little treatment other than avoidance of trauma to the skin. Patients with APD often undergo treatments aimed at controlling pruritus and the underlying systemic disorder with variable results. (See 'Reactive perforating collagenosis' above and 'Elastosis perforans serpiginosa' above and 'Perforating folliculitis' above and 'Acquired perforating dermatosis' above.)

●Treatment of acquired perforating dermatosis – Data on the treatment of APD are limited. Our initial approach consists of treatment of the underlying disease and measures to reduce pruritus, including camphor- or menthol-based lotions, bathing with gentle cleansers, and skin moisturization. Topical corticosteroids may provide additional relief from pruritus, when needed. Topical keratolytics or retinoids may help to improve the appearance of APD. Combination therapy may be helpful. Patients for whom these measures are insufficient may benefit from other treatments. (See 'Treatment' above.)