Acquired reactive perforating dermatosis

Authors


Correspondence to Dr. med. Gunnar Wagner, Klinik für Dermatologie, Allergologie und Phlebologie, Klinikum Bremerhaven Reinkenheide, Postbrookstrafle 103, 27574 Bremerhaven, Germany

E-mail: gunnar.wagner@klinikum-bremerhaven.de

Summary

Acquired reactive perforating dermatosis is characterized by umbilicated erythematous papules and plaques with firmly adherent crusts. Histopathological examination shows a typical cup-shaped ulceration in the epidermis containing cellular debris and collagen. There is transepidermal elimination of degenerated material with basophilic collagen bundles. The etiology and pathogenesis of acquired reactive perforating dermatosis are unclear. Metabolic disorders and malignancies are associated with this dermatosis. Associated pruritus is regarded as a key pathogenic factor. Constant scratching may cause a repetitive trauma to the skin. This pathogenesis may involve a genetic predisposition. The trauma may lead to degeneration of the collagen bundles. Treatment of acquired reactive perforating dermatosis follows a multimodal approach. Apart from the treating any underlying disease, treatment of pruritus is a major goal. Systemic steroids and retinoids, as well as UVB phototherapy are well-established treatment options. Some patients may also benefit from oral allopurinol.

Definition and Nosology

Acquired reactive perforating dermatosis (ARPD) is a rare disease with characteristic clinical findings which is classified as a primary perforating dermatosis. Diagnostic criteria include central hyperkeratotic or cup-like depressed necrotic papules, transepidermal elimination of basophilic collagen bundles, and manifestation in adults over 18 years of age [1, 2]. Diseases which are commonly associated with ARPD include diabetes mellitus, chronic renal insufficiency, and -hyperuricemia [1, 3, 4]. ARPD typically occurs in adults, and thus may be distinguished from hereditary reactive perforating dermatosis in children and adolescents [5].

Perforating dermatoses are a very mixed group of diseases clinically and histopathologically. They may be divided into in primary and secondary forms (Table 1). In primary perforating dermatoses, the main disease process consists of perforation of the dermoepidermal junction and transepidermal elimination of collagen or elastic fibers. In secondary perforating dermatoses, perforation and elimination of -connective tissue fibers (as well as other material) is an -occasional, more random phenomenon which occurs in another dermatosis with a different pathogenesis [6].

Table 1. Classification of perforating dermatoses [6, 32]
Primary perforating dermatosesSecondary perforating dermatoses as a special form occurring in:
▸ Hyperkeratosis follicularis et parafollicularis in cutem penetrans (Kyrle disease)▸ Granuloma annulare
▸ Elastosis perforans serpiginosa▸ Calcinosis cutis
▸ Reactive perforating dermatosis▸ Necrobiosis lipoidica
 hereditary▸ Chondrodermatitis nodularis chronica helicis
 acquired▸ Keratoacanthoma
 ▸ Other

Epidemiology

The prevalence and incidence of this rare dermatosis are -unknown [1, 7]. In the patient files at the Department of Dermatology, Bremerhaven Hospital, between 2007 and 2011, there were 10 cases of ARPD out of 5,202 hospitalized patients. Dermatology units at other hospitals report similar frequencies [4, 7]. The sex distribution is generally considered to be equal [1, 4]. Yet, Karpouzis and colleagues conducted a literature review of 101 patients and found a predominance of men (ratio of 1.5 : 1). At the time of diagnosis, the patient age ranged from 29–96, with an average age of 56.8 years. With 35 patients, peak frequency was in the 6th decade of life [3].

Etiology and Pathogenesis

There is no validated information available on the etiology and pathogenesis of ARPD. Suggested causes include a genetic predisposition, associated diseases (Table 2), and occasionally certain medications. In addition to various commonly associated metabolic disorders (including diabetes mellitus, chronic renal insufficiency, and hyperuricemia) [3, 4, 8], there have also been reports of other diseases occurring in patients with ARPD (Table 2). These include a range of thyroid and hepatic diseases of different origins [1, 3]. In addition, the number of malignant neoplasms appears to play a role; because both myeloproliferative and solid tumors have been reported, ARPD is considered be a few authors to be a facultative paraneoplastic disorder [3, 9]. There have also been repeated reports of ARPD after a scabies infection, herpes zoster, or an insect sting, although patients often also have diabetes mellitus or renal insufficiency [10-13]. Rarely, ARPD occurs after curettage of seborrheic keratosis [14]. In addition to disease-related causes, there are also occasional reports of a drug-induced etiology. Medications such as clopidogrel, which are broken down by hepatogenic cytochrome P450, may trigger ARPD in patients with abnormal liver function [15]. Indinavir and sirolimus have also been reported in conjunction with the onset of ARPD [16, 17]. The discussion on the pathogenesis of ARPD has also -focused on pruritus; this symptom is nearly always present in ARPD, but it also characterizes the associated diseases [1, 3, 18, 19]. The scratching causes microtrauma; in predisposed patients, it may be responsible for focal degeneration of the collagen fibers. Experiments have shown that microtrauma can trigger the clinical appearance of ARPD [6, 20, 21]. The pathogenetic relationship between pruritus, scratching, and the onset of ARPD lesions is supported by the localization of the lesions, which can always be reached with the hands, as well as the Köbner phenomenon, and improvement of clinical symptoms after successful antipruritic treatment [1, 18, 22]. In conjunction with skin traumatization, immunohistochemistry studies have shown the significance of growth factors and enzymes in the extracellular matrix, which are currently under discussion. Increased intralesional TGF-ß3 expression and increased intralesional fibroblast activity have been -demonstrated in ARPD [8, 23].

Table 2. Diseases associated with acquired reactive perforating dermatosis
Common
▸ Chronic renal insufficiency [1, 3, 4, 8, 39]
▸ Diabetes mellitus [1, 3, 4, 8, 39, 47]
▸ Hyperuricemia [3, 4, 8]
Rare
▸ Hypothyroidism [1]
▸ Hodgkin disease [1, 3, 10]
▸ Hepatocellular carcinoma [3, 10, 47]
▸ Thyroid cancer [10]
▸ Dermatomyositis [49, 50]

On a pathophysiological level, ARPD is characterized by hyaline degeneration of collagen fibers [12, 24]. Given that many patients also have diabetes, hyalinization may be due to glycation; in hyperglycemia there is increased -glycation of proteins and other compounds. The resulting metabolic products, or Maillard adducts, remain in proteins with a long half-life and change their physical/biochemical properties. This causes molecular cross-linking which impairs the solubility, susceptibility, and reaction ability of biological materials. In patients with chronic renal insufficiency, the elimination of the Maillard adducts is impaired, which is probably also important to the pathogenesis of ARPD. The microtrauma to the skin may trigger the elimination of altered collagen fibers [6, 25]. It is also possible that the diabetic microangiopathy is involved in this process, because it could promote the formation of necrotic zones within the lesions [22, 26].

Clinical findings

The clinical morphology of ARPD is characterized by umbilicated papules and plaques measuring 0.5–2.0 cm in diameter (Figures 1-4). Lesions may coalesce to form larger lesions (Figure 5), occasionally measuring up to 8 cm in diameter [27]. Along with an erythematous, often only ridge-like border, the clinical appearance is characterized by crusts which may be green-brown or have an oyster-shell-like black appearance; depressed or flat-elevated lesions are possible [4, 11, 19]. This results in a highly characteristic crater-like structure, which remains if there are erosions after the crusts detach (Figure 5). After the lesions heal, they leave atrophic, depressed, white or hyperpigmented scars [14, 27-29]. Predilection sites for ARPD include the trunk (Figure 1), especially the shoulder girdle (Figure 6), and the gluteal region as well as the extensor aspects on the upper and lower extremities [3, 4]. Based on data from 22 patients, Faver and colleagues reported manifestation rates of 64 and 77% (i.e., comparable rates) on the trunk and the extremities. Involvement of the head (mainly the scalp) was significantly less common, occurring in 22% of patients [1]. The palmoplantar regions, intertriginous areas, and mucous membranes, were unaffected. Lesions generally appear in groups when circumscribed areas of the skin are affected; when the entire surface area of the skin is involved, along with groups of lesions, in some areas there are also disseminated lesions [1, 4, 9]. The Köbner phenomenon is a common finding (Figures 7, 8). In the studies by Faver and colleagues, it was reported in 13 of 22 patients [1].

Figure 1.

Umbilicated erythematous papules and plaques with hemorrhagic crusts.

Figure 2.

Close-up view.

Figure 3.

ARPD lesion on darkly pigmented skin: central keratosis with hyperpigmented border.

Figure 4.

Close-up view.

Figure 5.

Solitary or confluent ARPD lesions, upper shoulder.

Figure 6.

Confluent ARPD lesions, upper shoulder.

Figure 7.

Köbner phenomenon in ARPD.

Figure 8.

Close-up view.

Patients nearly always report severe pruritus, often -describing it as excruciating [1, 4, 9]. Patients routinely have sudden “itching attacks”, repeatedly scratching the same area of skin.

Histopathology

The histological correlate is a well circumscribed area of -necrosis, which extends into the reticulated dermis, which is sharply bordered laterally by mild epithelial hyperplasia. -There is a wide basophilic crust of cellular detritus, abundant neutrophilic granulocytes, and collections of bacteria (Figure 9). On the ulcer base, there are collagen fiber bundles. These are often basophilic and stain with hematoxylin and eosin (H & E); they stain red with Van Gieson staining (Figure 10). The collagen fibers may be vertically aligned near the epidermis. Compared to the ulcerations, there is often a milder, superficial inflammatory infiltrate of mixed cells, containing a small number of lymphocytes, isolated neutrophilic granulocytes, and histiocytes [3, 7].

Figure 9.

Histology: well-defined ulceration with basophilic crust and epithelial hyperplasia in the periphery (H & E stain).

Figure 10.

Histology: red collagen fibers at the base of the ulcer (Van Gieson stain).

Differential diagnoses

The clinical appearance of ARPD is characteristic and is unmistakable, due to its typical morphology, localization, and distribution. In early-stage disease, in which only a few lesions are present (hence a lacking pattern of distribution), and rare or unusual localizations are affected, distinguishing ARPD from other perforating dermatoses may be a challenge. Hyperkeratosis follicularis et parafollicularis in cutem penetrans (Kyrle disease) is characterized by small, red-brown papules, which have a central keratin plug. There may be follicular or parafollicular papules. Predilection sites include the extensor aspects of the lower extremities [30]. In perforating folliculitis, there are erythematous, (only) follicular papules, which measure a few millimeters across and have a white, central keratotic plug. The lesions are disseminated and are mainly found on the hair-bearing extremity surfaces [31]. In both Kyrle disease and perforating folliculitis, the Köbner phenomenon is absent as are confluent papules. Serpiginous or annular, bright red papules and plaques, also with central keratosis, characterize the clinical appearance of elastosis perforans serpiginosa. In patients with symmetrical distribution, the disease typically affects the nape of the neck and the lateral neck areas [32-34]. Occasionally, diagnostic classification of disease as a primary perforating dermatosis is further complicated by the doubts expressed by some authors as to this being a separate disease entity, but rather a transitional appearance between two separate forms of disease [35-37]. Further differential diagnostic considerations may include secondary perforating dermatoses, other inflammatory dermatoses and solitary tumors [38].

Therapy

Treatment of ARPD can be challenging. It is usually -characterized by the employment of a wide range of treatment measures. An important requirement for successful dermatological treatment of ARPD is the management of any associated internal or oncological disease (Table 2). This includes the treatment of metabolic disorders, including optimal management of diabetes mellitus, effective dialysis, and if possible, curative treatment of existing solid or hematopoietic neoplasms [9, 40, 41].

Patients also require symptomatic treatment of the -usually severe pruritus. Topical remedies include urea-based, polidocanol, and capsaicin-based formulations; the dry skin must also be treated with an ointment base. For systemic treatment, antihistamines may be given, if necessary, in combination with several other agents [4]. Phototherapy is another option for treating pruritus; patients with ARPD usually receive UVB therapy [12, 42-44]. Phototherapy presumably also has direct anti-inflammatory and anti-proliferative effects [44]. Individual lesions are initially treated locally with keratolytic agents such as salicylic acid in a concentration of 5–7% in Vaseline, urea 10–15%, and tretinoin 0.01–0.1%; if necessary, the drugs may be applied under occlusion [4, 29, 40, 42, 43, 45]. After detachment of the crusts, and possibly curettage, treatment continues with class 2–3 corticosteroids; antiseptic agents may be given in addition [4, 15, 29, 46]. Intralesional injections of triamcinolone crystal suspension, or the application of topical retinoids, are further treatment options [15, 40]. For systemic treatment, corticosteroids and retinoids may be used [15, 40]. The results for allopurinol are contradictory. In a few patients, allopurinol therapy (100 mg daily) led to healing of ARPD; yet, there have also been patients in whom ARPD occurred, despite having been diagnosed with hyperuricemia, and receiving 300 mg allopurinol daily [4, 6, 14, 15]. An antioxidant effect of allopurinol is under discussion, as is possible elimination of urate-like crystals from the tissues [6, 14, 47]. In addition, there have been isolated reports of treatment of ARPD with roxithromycin, doxycycline, hydroxychloroquine, diphenyl sulfone (dapsone), and methotrexate [17, 20, 48, 49].

Acknowledgements

The histological images and details were provided courtesy of Christian Rose, MD, Dermatohistological Laboratory Lübeck,Germany.

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