Porokeratosis and immunosuppression

ARTICLE

The term "porokeratosis" (PK) encompasses a group of uncommon hereditary or acquired diseases of keratinization of unknown aetiology, presenting with varying clinical aspects but sharing a common histopathological aspect, characterised by the presence of the "cornoid lamella". PK was first described by Mibelli in 1893 [1]; several other clinical forms were subsequently identified. PK may appear in otherwise healthy persons but may also develop during the course of immunodeficiency states, among which organ transplantation seems to be the commonest. The general aspects of PK will first be dealt with, and the features that are particular to the forms appearing in the context of organ transplantation will then be discussed.

Porokeratosis: general features

Clinical manifestations

The primary lesion of PK is a dry, brownish keratotic papule which spreads slowly in a centrifugal fashion. Fully-developed lesions present as well-demarcated irregular plaques with a slightly atrophic centre, bordered by a peripheral, grooved, keratotic ridge, from which a keratotic core projects at an obtuse angle. According to the number, size and distribution of the lesions the following clinical forms of PK have been described:

a) Classic (or Mibelli) porokeratosis (PKM): this presents with one or a few annular plaques of large size (up to 20 cm). The lesions are usually unilateral but bilateral and symmetric lesions have been reported [2]. Giant lesions exist showing a highly raised peripheral border. In hereditary cases the lesions usually develop in childhood and enlarge slowly over the years, but in sporadic cases the lesions develop in adulthood. Men are more often affected than women (2.17:1). The lesions are usually asymptomatic and appear on the limbs, but may be located on the face [3] (including the lips) [2], the palms and soles, and rarely the genitalia or the buccal mucosa [4].

b) Linear porokeratosis (LPK) consists of a unilateral, linear, systematized lesion extending over the limbs, reminiscent of an epidermal naevus, linear psoriasis or lichen striatus. The lesions may appear on the trunk with a zosteriform distribution. The disease becomes manifest in infancy or childhood but may exceptionally appear in the elderly [5]. A slight female preponderance (1.63:1) has been observed.

c) Disseminated superficial actinic porokeratosis (DSAP): this seems to be the commonest form of PK and is more frequent in countries with high sun exposure. The lesions appear usually during the 3rd or 4th decade of life and are slowly progressive. A slight female preponderance has been noted (1.76:1), probably due to the fact that women are more likely to seek medical advice. DSAP manifests with several (up to hundreds of) small, dry, superficial annular lesions which appear in a bilateral and symmetric fashion on sun-exposed areas of the body, mainly the extensor surfaces of the limbs (Figs. 1 and 2), shoulders and the back, more rarely the face. Individual lesions are less prominent than those of PKM and may be overlooked by the patients or mistaken by physicians for actinic or flat seborrheic keratoses, stucco keratoses, annular lichen planus or granuloma annulare. At least half of the patients experience exacerbations during the summer months as a consequence of sun exposure [6] or after exposure to artifical light (UVA, UVB) [7-9]; one third of them experience pruritus or stinging sensations.

d) Disseminated superficial porokeratosis (DSP): this is clinically similar to DSAP, except that UV light does not act as an eliciting factor; the lesions are therefore located both on sun-exposed and sun-protected sites, and may be pruritic [10].

e) Porokeratosis palmaris, plantaris et disseminata (PPPD) is characterized by the development of symmetrical, bilateral, red-brown keratotic papules resembling those of DSAP. It affects predominantly (2:1) males. The lesions appear in adolescence or early adulthood initially over the palms and soles but may later involve other body areas including sun-exposed and sun-protected sites (limbs and trunk) [11]. The buccal mucosa may be affected with small opalescent ring-like lesions [12].

g) Punctate porokeratosis (PPK) is limited to the palms and soles and manifests with numerous punctate, keratotic seed-like plugs that mimick "spines of an old-fashioned music box" [13]. This variant should be distinguished clinically from lesions of the naevoid basal-cell naevus syndrome, Darier's disease, palmoplantar lichen nitidus and hereditary punctate keratoderma. The lesions may be moderately tender to pressure. PPK may be associated with PKM or LPK.

Finally, some other forms have been described, reflecting the variability of the clinical presentation of PK, such as "reticulated" PK [14], and "eruptive pruritic" PK [15]. The relationship of PK with other conditions, such as porokeratotic eccrine and ostial dermal duct naevus, porokeratosis punctata palmaris et plantaris, punctate porokeratotic keratoderma, is unclear.

Aetiology and pathogenesis

The aetiology and pathogenesis of PK are obscure but certainly complex and multifactorial. It has been suggested that the lesions of PK result from the peripheral expansion of an abnormal, mutant clone of epidermal keratinocytes (that would be inherited) located at the base of the parakeratotic column [16]. This attractive hypothesis is supported by the cytological finding of abnormal DNA ploidy [17], the increased proportion of keratinocytes in the S and G2/M phases of the cell cycle [18], as well as by the overexpression of the p53 oncoprotein [19, 20] and of proliferation-associated antigens within keratinocytes in the vicinity of the cornoid lamella [20, 21]; it is in accordance with the results of experimental studies, showing that autotransplantation of normal skin into the border of a DSAP lesion results in the formation of a pathologic ridge within the graft, whereas this disappears from a lesion grafted onto normal-looking skin [6]. The following (eliciting or triggering) factors have been considered to play a role in the genesis of lesions:

a) Genetic factors: these are certainly important since several familial cases of PKM, DSAP, PPPD and PPK have been reported. The mode of inheritance is autosomal dominant with reduced penetrance [22]. The similarities in the clinical and histological appearance of all forms of PK and the possible coexistence of different forms within the same family [23] suggest that the various PK forms are different phenotypic expressions of a common genetic defect. The sporadic cases reported could be due to somatic mutations. In vitro studies have shown chromosomal abnormalities in cultured fibroblasts and lymphocytes, concerning namely chromosome 3 (p12-14) [24].

b) Ultraviolet (UV) light: at least in DSAP, UV light plays a major role. This is suggested by clinico-epidemiological data (development of lesions on sun-exposed areas, exacerbation of the disease during the summer, PUVA-induced cases, predominance of DSAP in geographic areas with high sun exposure, appearance of the lesions in adulthood), and has been shown experimentally after UV exposure [7, 9]. However, in vitro studies have shown that cultured fibroblasts from PK patients are hypersensitive to X-ray but (curiously) not to UV radiation [25], and one case of PK improved with PUVA treatment [26]; these facts, along with the scarcity of facial lesions in PK [27], cast some doubt on the predominant role of UV light in the genesis of lesions. On the other hand, electron-beam radiation also seems to act as a triggering factor [28].

c) Trauma: the development of PK in a burn scar [29] or the access region for haemodialysis [30] suggests that the isomorphic (Koebner) phenomenon could play a role in the development of lesions; however, attempts to deliberately induce lesions have failed [6].

d) Infectious agents: these were suspected because of the development of PK under immunosuppressive treatments, that could reactivate a putative virus [31]; however, attempts for animal inoculation have proven unsuccessful [6].

e) Immunosuppression: after the initial observation of PKM developing in a renal transplant recipient [31], several cases of PK have been reported in the course of immunodeficiency diseases (Table I). These include mainly organ transplantation [31-52] (see below), haemopoietic malignancies and lymphomas [28, 33, 49, 53-58], HIV infection [20, 59] and various inflammatory or autoimmune diseases usually treated with immunosuppressive drugs or chemotherapy [33, 60-71]. In several of these cases the course of PK clearly paralleled the level of immunosuppression [31, 33, 34, 56, 59], and in two cases the disease regressed completely after discontinuation of immunosuppressive treatment [51, 65]. These observations clearly highlight the promoting role of immunosuppression, but its precise mode of action remains unknown. Immunosuppression could induce decreased immune surveillance, which would prevent pathologic keratinocyte clones from being recognised and immunologically rejected; alternatively, it could directly trigger the development and proliferation of a mutant clone of keratinocytes. On the other hand (local) immunosuppression could probably also explain the promoting effect of UV light.

In summary, the most widely accepted theory explaining the development of PK is that the lesions are due to the expansion of a mutant clone of epidermal keratinocytes, that could be inherited. The abnormal clone would normally be controlled by immune mechanisms, and its expansion promoted by a number of triggering factors, such as UV light or immunosuppression (be it disease-related or iatrogenic). This hypothesis still needs unequivocal confirmation.

Histopathology

Histologically, the central part of PK lesions shows a hyperkeratotic, usually thin epidermis with flattened rete ridges. The epidermis may rarely be acanthotic. The underlying dermis usually harbours a mild perivascular mononuclear-cell infiltrate. The most characteristic changes are seen at the periphery of the lesion, at the level of the keratotic border: the horny layer is orthokeratotic and thickened, and contains a narrow vertical stack of corneocytes containing pyknotic nuclei. This parakeratotic column (cornoid lamella) is seated on a dell of the underlying epidermis (Fig. 3), extending downwards at an angle the apex of which points away from the centre of the lesion. At the level of the cornoid lamella, the granular layer is usually interrupted; the malpighian layer contains cells with perinuclear oedema and cells with an eosinophilic cytoplasm (dyskeratotic keratinocytes). The corresponding basal cell layer may show hydropic degeneration. The superficial dermis contains a mononuclear cell infiltrate of mild to moderate degree, that may come in contact with the basal cell layer of the epidermis, resulting in a lichenoid aspect; it consists predominantly of activated T helper cells [72, 73]. Eosinophils [15], colloid bodies and amyloid deposits [10] may rarely be found in the papillary dermis, and rare cases showing eosinophilic spongiosis have been described [67]. The most pronounced changes are found in lesions of PKM; in the other forms (namely the DSAP) the cornoid lamella may be less prominent (the parakeratotic stack is usually smaller and the central invagination in which it is seated more shallow). Occasionally, the cornoid lamella corresponds to ostia of eccrine glands or hair-follicles, which led to the misnomer "porokeratosis"; however, this finding is fortuitous, since the peripheral border of PK lesions is moving centrifugally and therefore it cannot be permanently bound to epidermal adnexae (that are definite structures); moreover, the occurrence of lesions over mucous membranes further shows that PK lesions do not necessarily develop within epidermal adnexae.

The histological aspect PK is characteristic and allows confirmation of the diagnosis. It should be borne in mind, however, that the cornoid lamella is not absolutely specific PK since it can be seen, although rarely, in premalignant keratoses, basal and squamous cell carcinomas, seborrheic keratosis and viral warts [74].

Electron microscopy reveals, underneath the cornoid lamella, a decrease of keratohyalin granules and lamellar bodies, a finding that could account for the defective desquamation of corneocytes. In the malpighian layer, keratinocytes show signs of degeneration, such as cytoplasmic vacuoles and peripheral condensation of tonofilaments [20, 76]. Dyskeratotic cells contain aggregated tonofilaments [76]. The parakeratotic cells of the cornoid lamella contain pyknotic nuclei and an electron-dense cytoplasm due to the presence of degraded organelles and lipid droplets [20]. The expression of filaggrin is reduced, reflecting the decrease of the granular cell layer, but that of involucrin is increased [20, 21, 75]. Epidermal Langerhans cells are usually diminished in number [20, 44].

Course

The lesions of PK progress slowly, increasing in size and number over the years; on rare occasions they may undergo inflammatory changes and regress spontaneously [15, 77]. As stated above, immunosuppression-associated PK may fluctuate in parallel with the level of immunosuppression, and complete regression has been reported after discontinuation of immunosuppressive treatment [51, 65]. In some cases, the PK lesions may undergo malignant transformation to Bowen's disease, squamous cell and (more rarely) basal cell carcinoma [78-80]. A review of 281 cases of PK published in the English literature showed that malignant transformation occurred in 7.5% of patients [80]; remarkably, none of them occurred in immunosuppressed patients. Large lesions (namely of the extremities), those of long-standing duration and linear PK seem to be at greater risk, whereas DSAP has a much lower risk [27, 80]. Malignant lesions are usually single, but multiple tumours may develop in one third of cases. The duration of the disease is longer in patients presenting with malignancy (33.5 vs 13.7 years) [80]. Metastasis to lymph nodes and a fatal outcome have also been reported [81]. In Japanese patients the risk of malignant transformation may be even higher (11.6%) [79]. PK is therefore often considered as a premalignant condition. The finding of increased chromosomal instability in fibroblasts from non-affected skin and also in peripheral blood lymphocytes [24, 25] suggests the possibility of an increased susceptibility to malignancy in general.

Treatment

Several treatments have been proposed for PK but the response is variable and often disappointing; the treatment is therefore palliative rather than curative [82]. Locally, lubricating or keratolytic agents, 5-fluorouracil, tretinoin, and steroids can be tried. Recently, significant improvement was obtained in three patients with DSAP with topical calcipotriol [83]. Isolated lesions can be excised surgically or treated with cryotherapy, electrodessication, dermabrasion or CO₂ laser. Systemic retinoids can be tried in diffuse forms and may prove effective [84, 85]; however, relapses are common and exacerbations during this treatment have also been noted [86]. Photoprotection with sunscreens should be prescribed for patients with DSAP to prevent worsening of the lesions.

Porokeratosis after organ transplantation

Following the initial report of MacMillan & Roberts in 1974 [31], several cases of PK were reported after organ transplantation; our review of the literature revealed a total of 62 such cases, including kidney (n:44), heart (n:9), bone-marrow (n:5), lung (n:3) and liver (n:1) transplantation (summarised in Table II). PK associated with organ transplantation represents by far the commonest type of immunosuppression-associated PK.

The incidence of PK after organ transplantation varies considerably among the different series. In most retrospective studies it is usually low, having been estimated to 0.34% [86], 0.54% [36], 0.66% [40], 1.07% [33], 1.87% [48] or 3.4% [87]; however, a study performed prospectively in a series of renal-graft recipients [39] found a much higher incidence (10.68%). The difficulty in precisely estimating this incidence may be due to several reasons: firstly, the lesions may be both overlooked by patients (who seldom seek spontaneously advice for them) [39] and either pass unnoticed by physicians, or mistaken for solar keratoses [27]; secondly, as happens with other premalignant skin conditions, it can be speculated that the incidence of PK will increase with time after transplantation, so that the heterogeneity of the groups studied could account for the different results reported. Although the published series are small and do not allow definitive conclusions, it seems that patients having received organ transplants other than the kidney (lung or heart) develop PK relatively more often than kidney-transplant recipients [36, 37]; it can reasonably be speculated that this is because non-kidney transplant recipients receive more intensive immunosuppressive treatments.

The delay of appearance of PK following organ transplantation varies between 4 months and 14 years; in kidney-transplant recipients, who represent 72% of all reported organ-transplant recipients with PK, the average delay is around 4-5 years (one kidney-transplant recipient was reported to suffer from abrupt and extensive eruption of PK two weeks following transplantation, but this patient probably had preexisting PK so that this case most likely represents exacerbation of preexisting disease rather than de novo development) [31]. The delay of appearance is shorter (usually less than 3 years) after transplantation of other organs (liver, lung, heart and bone-marrow), a finding that would further highlight the promoting role of immunosuppression.

Clinically, PK in organ-transplant recipients manifests with multiple and more rarely single lesions, located on the legs in the majority of cases. The prevalent clinical forms therefore correspond either to DSP or to PKM. Histologically, immunosuppression-associated PK shows no significant differences from cases appearing in immunocompetent individuals [37].

From a pathogenetic point of view, genetic factors do not seem to be of major importance in immunosuppression-associated PK, since none of the reported transplant recipients with PK had family history of the disease. A decreased expression of HLA-DR antigens by epidermal Langerhans cells has been observed within PK lesions of renal-transplant recipients, and it has been speculated that this defective expression could account for failure of local immunosurveillance, contributing to the development of abnormal keratinocyte clones [44]. In one study it was suggested that exposure to sunlight was not a major factor for the development of PK, contrasting with PK developing in non-immunosuppressed patients [33]; however cases of renal-transplant recipients developing lesions under the influence of sun-exposure have also been reported [39, 41].

As in "idiopathic" cases, the course of PK in the setting of immunosuppression is slowly progressive. Usually more lesions continue to appear in affected areas but lesions do not develop in previously unaffected areas [33]. Substitution of cyclosporine A by azathioprine and steroids resulted in one case in partial regression of the lesions [34], but there is no firm evidence to suggest that any of the commonly used immunosuppressive drugs is more likely to induce the development of PK than another. In one bone-marrow graft recipient the disease regressed completely after discontinuation of the immunosuppressive treatment [51], highlighting the important role of immunosuppression. Curiously, another patient who received a liver transplant (performed for end-stage liver disease) experienced regression of PK after transplantation [68]; however it seems likely that in this case PK had been induced by liver dysfunction that was restored after grafting. No long-term follow-up of this particular patient has been reported, but it can be anticipated that PK would recur under long-term immunosuppressive treatment.

The fact that so far no malignant degeneration in immunosuppression-associated PK has been observed is puzzling, all the more so given that transplant recipients are at highly increased risk for developing cutaneous malignancies as compared to the general population. A possible explanation could be the relatively short follow-up time, since malignant transformation occurs in classical PK after an average of 33.5 years [80]; furthermore, DSAP (one of the most frequent forms of PK in organ-transplant recipients) has a low-risk of malignant transformation. Therefore, and despite the fact that lesions may be resistant to treatment, we believe it prudent to remove surgically or destroy (e.g. by cryotherapy) lesions of PK in organ-transplant recipients. On the other hand, the development of PK in an organ-transplant recipient should prompt a close dermatological surveillance [88] since these patients develop (more or less concomittantly) other cutaneous premalignant (actinic keratoses, Bowen's disease) and malignant lesions (basal and squamous cell carcinomas).

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