Porokeratosis

INTRODUCTION — Porokeratosis is a rare, acquired or inherited disorder of keratinization characterized by one or more atrophic macules or patches, each surrounded by a distinctive hyperkeratotic, ridge-like border called a "cornoid lamella" (picture 1A-B) [1,2]. Multiple clinical variants of porokeratosis exist. Malignant transformation occurs in a minority of cases.

Although clinical surveillance for malignant transformation is sufficient for the management of most patients with porokeratosis, patients who are concerned about the appearance of lesions or who have associated symptoms, such as pruritus or pain, may desire therapeutic intervention. Formal studies of the therapeutic options for porokeratosis are lacking, but various topical, surgical, destructive, and systemic therapies appear to be effective in some patients.

The pathogenesis, clinical manifestations, diagnosis, and management of porokeratosis will be reviewed here.

EPIDEMIOLOGY — Porokeratosis is a rare disease. The exact incidence and prevalence are not known. It typically occurs in adults or older adults with slight male predominance, but pediatric cases have been reported [3-7].

CLASSIFICATION — The most commonly described variants of porokeratosis include:

●Disseminated superficial actinic porokeratosis (DSAP1; MIM #175900, 616063, 614714, 616631)

●Disseminated superficial porokeratosis (DSP; MIM #175900, 616631)

●Eruptive disseminated porokeratosis

●Porokeratosis of Mibelli (MIM #175800)

●Linear porokeratosis

●Porokeratosis palmaris et plantaris disseminata (PPPD; MIM #175850)

●Punctate porokeratosis (sometimes considered a variant of PPPD)

●Porokeratosis ptychotropica

●Genitogluteal porokeratosis

Most clinical types of porokeratosis can manifest in localized or generalized forms; however, overlap between the forms as well as clinical variants are not uncommon.

PATHOGENESIS — The clonal proliferation of abnormal epidermal keratinocytes is believed to account for the clinical manifestations of porokeratosis. However, the pathway that leads to this process remains unknown. A variety of factors have been proposed as potential contributors, including genetic susceptibility, ultraviolet radiation, and immune status.

Genetics — Inherited or de novo genetic defects likely play an important role in porokeratosis. Studies in familial cases of disseminated superficial actinic porokeratosis (DSAP) support an autosomal dominant inheritance pattern with incomplete penetrance [8].

Four potential chromosomal loci for DSAP have been identified, including DSAP1 (12q23.2-24.1), DSAP2 (15q25.1-26.1), DSAP3 (1p31.3-p31.1), and DSAP4 (16q24.1-24.3) [9-12]. In Chinese studies, mutations in the phosphomevalonate kinase pathway genes, namely mevalonate decarboxylase (MVD), mevalonate kinase (MVK), phosphomevalonate kinase (PMVK), and farnesyl diphosphate synthase (FDPS), have been detected in some patients with porokeratosis [13,14]. There are over 200 mutations identified so far [14-17]. At least one mutation in the mevalonate pathway genes was reported to be found in up to 98 percent of the familial and over 70 percent of sporadic porokeratosis cases [18].

The mevalonate pathway genes are involved in the biosynthesis of isoprenoids, which are precursors of multiple biologically important substances, such as cholesterol, and are indirectly involved in biologic events, such as cell growth of differentiation. It is thus hypothesized that mutations in mevalonate pathway result in accumulation of abnormal cell metabolites, retention of cell nuclei in the epidermis, and formation of the cornoid lamella [18,19]. Moreover, inhibition of enzymes within the mevalonate pathway leads to decreased expression of keratinocyte differentiation marker involucrin, p53 and Notch1, further supporting the causative relationship between mutations in mevalonate pathway and development of porokeratosis [20].

Familial cases of disseminated superficial porokeratosis (DSP) and porokeratosis plantaris palmaris et disseminata (PPPD) demonstrate autosomal dominant inheritance patterns. The loci linked to DSP and PPPD are on chromosome 18p11.3 and chromosome 12q24.1-24.2, respectively [21-23].

Focal forms of porokeratosis, such as porokeratosis of Mibelli and linear porokeratosis, may occur as a consequence of mosaicism. The occurrence of linear porokeratosis or porokeratosis of Mibelli in patients with DSAP has been attributed to this theory [8,24]. In such cases, focal loss of heterozygosity via somatic mutations may result in the prominent, localized clinical manifestations that characterize linear porokeratosis and porokeratosis of Mibelli, while the relatively milder manifestations of DSAP appear in a generalized distribution [8,24,25]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Mosaicism'.)

Ultraviolet radiation — Exposure to ultraviolet radiation may contribute to the development of porokeratosis. This assertion is supported by the observation that DSAP preferentially occurs on areas of exposed skin and in individuals with histories of extensive sun exposure. In addition, the administration of artificial ultraviolet light in experimental and therapeutic settings has resulted in the induction of DSAP lesions [26-29].

Despite these findings, a definitive role for ultraviolet radiation in porokeratosis remains uncertain. Improvement in DSAP after treatment with psoralen plus ultraviolet A (PUVA) therapy has been documented in one patient [30]. The relative sparing of the face in DSAP also raises questions about the designation of ultraviolet radiation as a contributory factor. (See 'Disseminated superficial actinic porokeratosis' below.)

Immunosuppression — Drug-induced immunosuppression or immunodeficiency in the setting of nonmalignant diseases or hematologic malignancy may increase the risk for porokeratosis [31-37]. Estimates of the prevalence of porokeratosis in immunosuppressed organ transplant recipients range from less than 1 percent to as high as 11 percent [33,36].

Porokeratosis has occurred 3 weeks to 14 years after the initiation of systemic immunosuppression [36,38]. DSP and porokeratosis of Mibelli are the most commonly associated variants [39]. A rapidly evolving form of porokeratosis, called eruptive disseminated porokeratosis, has been described in older patients, in association with solid cancers or immunosuppressive therapy [40].

New-onset DSP and porokeratosis of Mibelli have been reported in patients with known HIV infection and may indicate a worsening of the immunodeficiency [32,41].

A contributory role for immunosuppression is supported by reports of remission of porokeratosis after cessation of immunosuppressive therapy in two patients [42,43]. The development of porokeratosis in sites of long-term potent topical corticosteroid use in another patient also suggests a role for immunosuppression [44].

Other — Additional factors that have been associated with porokeratosis include radiation therapy [45,46], trauma [47], liver disease [48,49], solid organ cancer [50,51], and Crohn's disease [52]. Cases of drug-induced porokeratosis have also been reported following treatments with nivolumab and hydroxyurea [53-55].

CLINICAL PRESENTATION — The defining feature of porokeratosis is the clinical and histopathologic presence of a cornoid lamella, which typically manifests as a thin, keratotic rim at the periphery of a slightly atrophic skin lesion (picture 1B). Lesions typically begin as small, keratotic papules that spread slowly and centrifugally [39].

Multiple clinical variants have been described. Disseminated superficial actinic porokeratosis (DSAP) is generally accepted to be the most common variant, followed by porokeratosis of Mibelli. In one series of 94 patients in Singapore, classic porokeratosis of Mibelli, DSAP, disseminated superficial porokeratosis (DSP), and linear porokeratosis accounted for 56, 18, 11, and 13 percent of cases of porokeratosis, respectively [5].

Disseminated superficial actinic porokeratosis — Disseminated superficial actinic porokeratosis (DSAP) is the most common type of porokeratosis. DSAP occurs more frequently in women than men, with an estimated female to male ratio of approximately 1.8:1 [39]. The onset of disease typically occurs in the third or fourth decade of life, and patients frequently report a history of extensive exposure to natural or artificial ultraviolet radiation. Worsening of disease during the summer months may occur [39].

DSAP is characterized by erythematous, skin-colored or hyperpigmented, well-defined macules that are typically less than 1 cm in diameter (picture 2A-C). The cornoid lamella is often subtle, manifesting as a fine, peripheral, keratotic ridge. The distribution of lesions typically involves the extensor surfaces of the arms, legs, shoulders, or back, with sparing of the palms and soles. Facial lesions, a less common finding, occur in approximately 15 percent of patients [56]. A less common variant (inflammatory DSAP) presents as erythematous lesions, accompanied by inflammation and severe pruritus [57].

The number of skin lesions in DSAP is variable. Only a few or several hundred lesions may be present [30]. The cosmetic appearance of DSAP is a common concern for patients with this disorder and may be particularly bothersome for individuals who frequently wear skirts or shorts that expose the lower legs. Skin lesions are often asymptomatic, but pruritus or stinging sensations are estimated to occur in one-third to one-half of patients [30,39].

Disseminated superficial porokeratosis — Disseminated superficial porokeratosis (DSP) resembles DSAP but lacks photodistribution, appearing in both sun-exposed and non-sun-exposed sites. Like DSAP, the palms and soles are typically spared.

In contrast to DSAP, DSP often develops in childhood, most commonly between the ages of 5 and 10 years [39]. As noted above, DSP also can occur in association with immunosuppression [58-60] (see 'Immunosuppression' above). In addition, DSP has been reported in a few patients with solid organ malignancies [50,51].

Eruptive disseminated porokeratosis — The term "eruptive disseminated porokeratosis" has been proposed for adult-onset, acute disseminated porokeratosis, which has a male preponderance and may show variable morphology [40]. Most patients with adult-onset DSP are immunosuppressed or have a coexisting internal malignancy.

Porokeratosis of Mibelli — Porokeratosis of Mibelli is the second most common type of porokeratosis [3]. The disorder often begins in childhood and affects males approximately twice as frequently as females [39]. Occasionally, lesions develop during adulthood, often in association with immunosuppression [32,34,36,61].

Porokeratosis of Mibelli typically begins as a small, asymptomatic or slightly pruritic papule that slowly expands over the course of years (picture 1A, 1C-D). Faster growth may occur in the setting of immunosuppression. Well-developed lesions are usually a few centimeters in diameter, and, rarely, lesions grow to 10 to 20 cm in size. The term "giant porokeratosis" has been used to describe these exceptionally large lesions [62,63]. The cornoid lamella is often prominent in lesions of porokeratosis of Mibelli. The lesion border is usually greater than 1 mm in height, and a thin furrow is typically seen in the center of the ridge, causing an appearance that resembles the Great Wall of China (picture 1C). The center of the lesion may be slightly hypopigmented or hyperpigmented, minimally scaly, slightly atrophic, and hairless. Uncommonly, lesions manifest as confluent, hyperkeratotic or verrucous, thick plaques [64,65].

The classic location for porokeratosis of Mibelli is on an extremity. However, lesions may occur in any site, including the palms, soles, genitalia, or mucous membranes [39,66,67]. Patients usually present with a solitary lesion or a few asymmetrically distributed lesions. Occasionally, widespread lesions occur [24,62,64]. Involvement of the distal portions of fingers and toes may result in dystrophy and/or complete loss of the nail [68].

Linear porokeratosis — Linear porokeratosis is a rare form of porokeratosis that may represent a segmental form of DSAP or DSP [8,24]. The skin lesions typically present during infancy or early childhood but occasionally develop in adults. Females are slightly more likely to be affected than males [36].

Based on the distribution of the lesions, linear porokeratosis can be subdivided into localized, zosteriform, systematized, or generalized variants (picture 3A-B):

●Localized – The localized variant of linear porokeratosis presents as single or multiple plaques with hyperkeratotic, peripheral rims on one extremity. The lesions may initially be flat and become more prominent with time. As in porokeratosis of Mibelli, the hyperkeratotic border is often prominent, and a furrow is seen just inside of the hyperkeratotic ridge.

●Zosteriform – In the zosteriform variant, the configuration of lesions usually follows the lines of Blaschko (figure 1).

●Systematized – Systematized linear porokeratosis presents as lesions distributed on the upper and lower extremities of one body side.

●Generalized – In the generalized form of linear porokeratosis, lesions are found on more than one extremity or on the trunk.

Linear porokeratosis is associated with increased risk of squamous cell carcinoma [69-72]. (See 'Malignant transformation' below.)

Porokeratosis plantaris palmaris et disseminata — Porokeratosis plantaris palmaris et disseminata (PPPD) is a rare variant of porokeratosis, inherited in an autosomal dominant pattern, that may develop at any age [3,73]. Lesions customarily first appear in adolescence or early adulthood.

The initial manifestations of PPPD are multiple small, relatively uniform macules on the palms and soles that exhibit a slightly hyperpigmented and atrophic center and a minimally raised peripheral ridge [73-76]. A serpiginous configuration may evolve over time. Patients with PPPD can also develop lesions on the trunk and extremities that resemble lesions of DSAP and DSP (picture 4). Involvement of the oral mucosa may also occur as multiple small, depressed, opalescent rings with hyperemic borders [77].

The lesions of PPPD may be asymptomatic, pruritic, or tender to palpation. Porokeratoses on the feet may cause discomfort with walking.

Punctate porokeratosis — Punctate porokeratosis (porokeratosis punctata palmaris et plantaris) is characterized by multiple small, seed-like, keratotic lesions on the palms and soles (picture 4) that have histopathologic findings consistent with a cornoid lamella [78,79]. Some authors consider punctate porokeratosis to be a forme fruste of PPPD rather than a separate entity.

Porokeratosis ptychotropica — Porokeratosis ptychotropica is an unusual psoriasiform variant of the disease, also described as verrucous and hypertrophic porokeratosis [80-82]. This type of porokeratosis typically presents in male patients with inflammatory, keratotic, or verrucous plaques on the buttocks or genital skin (picture 5A-B). Pathology shows numerous histopathologic foci of cornoid lamellae [80,81,83]. Lesions of porokeratosis ptychotropica are often mistaken for psoriasis, lichen simplex chronicus, or chronic eczema not only due to clinical similarities but also due to itching.

Genitogluteal porokeratosis — The genital area is uncommonly affected by porokeratosis, with approximately 50 cases reported in the literature [84]. The porokeratotic lesions in the genital area can either represent a separate entity or a localized form of other types of porokeratosis [85]. The genital involvement is more commonly reported in men; however, case reports of vulval porokeratosis have also been published.

Over 10 cases of penoscrotal porokeratosis have been published [86,87]. In this variant, the patients develop solitary or multiple lesions of variable size limited to the penile and/or scrotal skin. This uncommon variant of the disease has been reported to only occur in young men in their third decade of life, with clinical manifestation on the penile shaft and anterior scrotum accompanied by severe burning and itching (picture 6) [85].

Other — Other subtypes of porokeratosis that have been described in the literature include follicular porokeratosis [88-91], eruptive pruritic papular porokeratosis in the setting of DSP [92-94], giant porokeratosis (see 'Porokeratosis of Mibelli' above), filiform porokeratosis [95], and porokeratosis associated with CDAGS (craniosynostosis, delayed closure of the fontanel, cranial defects, clavicular hypoplasia, anal and genitourinary malformations, and skin eruption) syndrome [96,97].

MALIGNANT TRANSFORMATION — Malignant transformation may occur in patients with all clinical variants of porokeratosis, with the exception of punctate porokeratosis [98]. It is estimated to occur in 7.5 to 11 percent of patients, with an average period to cancer onset of 36 years [39]. Squamous cell carcinoma is the most common associated malignancy [99]. Basal cell carcinoma and Bowen disease (squamous cell carcinoma in situ) may also occur.

Linear porokeratosis and giant porokeratosis (a variant of porokeratosis of Mibelli) are the variants most susceptible to malignant transformation, while this occurrence in disseminated superficial actinic porokeratosis (DSAP) is less common [98,100,101]. One review of 281 patients with porokeratosis found risks for malignant transformation in patients with linear porokeratosis, porokeratosis plantaris palmaris et disseminata (PPPD), porokeratosis of Mibelli of any size, and DSAP of 19, 10, 8, and 3 percent, respectively [98]. However, as development of DSAP might be ultraviolet light dependent and ultraviolet irradiation causes development of cutaneous malignancies, concurrent presentation of DSAP, actinic keratoses, and other cutaneous malignancies is not infrequent. Large lesion size, location on the extremities, and long lesion duration are additional factors that have been identified as risk factors for malignant transformation [39,98,102,103].

DIAGNOSIS — Due to a distinct clinical presentation, diagnosis is often made by clinical inspection. Dermoscopy can support the clinical diagnosis [104]. However, histology along with clinical suspicion provides the most accurate diagnosis.

Clinical — The diagnosis of porokeratosis often can be made based solely on clinical examination. The clinical appearance of an atrophic macule or patch with a well-defined, raised, hyperkeratotic ridge suggests this disorder (picture 1B). Marker ink or iodine can be used to highlight the appearance of the cornoid lamella in subtle cases. Self-tanning lotions containing dihydroxyacetone also highlight the cornoid lamella.

Skin biopsies usually are not necessary. Biopsies are typically performed when the appearance of the lesion is not classic or when there is concern for malignant transformation. (See 'Histopathology' below and 'Differential diagnosis' below.)

Histopathology — A shave biopsy deep enough to incorporate the mid-dermis is adequate for diagnosis, provided that it includes the edge of the lesion (site of the cornoid lamella). Small lesions may be removed entirely by shave excision. A punch biopsy of the lesion edge may also be performed. (See "Skin biopsy techniques", section on 'Biopsy techniques'.)

The classic histopathologic feature of porokeratosis is the cornoid lamella, a thin column of tightly packed parakeratotic cells within a keratin-filled epidermal invagination (picture 7A-C). The apex of the column angles away from the center of the lesion, and the base of the column demonstrates interruption of the epidermal granular layer and dyskeratotic keratinocytes [36]. A moderate lymphocytic inflammatory infiltrate is typically present in the papillary dermis. Dermal amyloid deposits are occasionally seen [80,105,106]. Melanocytic hyperplasia, with or without clinical hyperpigmentation, was noted in approximately 25 percent of specimens in one study [107].

Although the vast majority of biopsy specimens that demonstrate a cornoid lamella are derived from true porokeratoses, the finding is not exclusive to these lesions. Rarely, cornoid lamellae may be seen in other disorders, such as actinic keratoses, seborrheic keratoses, viral warts, and basal cell or squamous cell carcinoma [108].

Dermoscopy — Dermoscopy is a noninvasive test that can be useful for diagnosis if the clinician has access to the equipment and is trained in its use. (See "Overview of dermoscopy".)

The most distinct dermoscopic feature is the keratin rim (the cornoid lamella) [104], which appears as a thin, white, double-marginated rim [109-113]. The atrophic center of a lesion often demonstrates a white area with glomerular or dotted vessels [104,109]. The less common dermatoscopic features involve nonperipheral scales, gray-brown dots, and pigmentation along or within the keratin rim [104].

Additional evaluation — The possibility of associated immunosuppression or internal malignancy (especially hematologic malignancy) should be considered in adults who present with new-onset porokeratosis of Mibelli or porokeratosis plantaris palmaris et disseminata (PPPD), or sudden exacerbations of a longstanding porokeratotic disorder.

DIFFERENTIAL DIAGNOSIS — The detection of a cornoid lamella on clinical examination in a lesion suspicious for porokeratosis is usually sufficient for diagnosis. However, when patients present with less classic findings, other disorders that share clinical features with porokeratosis must be considered. In such cases, a biopsy of the lesion for histopathologic evaluation is helpful for distinguishing between porokeratosis and other disorders:

●Disseminated superficial actinic porokeratosis – Lesions that clinically may resemble disseminated superficial actinic porokeratosis (DSAP) or disseminated superficial porokeratosis (DSP) include:

•Multiple actinic keratoses (picture 8) (see "Actinic keratosis: Epidemiology, clinical features, and diagnosis")

•Macular seborrheic keratoses (picture 9) (see "Overview of benign lesions of the skin", section on 'Seborrheic keratosis')

•Inflammatory skin disorders, such as guttate psoriasis, pityriasis rosea, nummular dermatitis, tinea corporis, and lichen planus (picture 10A-E) (see "Guttate psoriasis" and "Pityriasis rosea" and "Nummular eczema" and "Dermatophyte (tinea) infections", section on 'Tinea corporis' and "Lichen planus")

●Porokeratosis of Mibelli – Lesions that clinically may resemble porokeratosis of Mibelli include:

•Cutaneous squamous cell carcinoma in situ (picture 11) (see "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis")

•Tinea corporis (picture 10D) (see "Dermatophyte (tinea) infections")

•Granuloma annulare (picture 12) (see "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis")

•Lichen simplex chronicus

•Circumscribed palmar or plantar hypokeratosis [114]

•Cutaneous sarcoidosis [115] (see "Cutaneous manifestations of sarcoidosis")

●Linear porokeratosis – Lesions that clinically may resemble linear porokeratosis include:

•Linear warts (see "Cutaneous warts (common, plantar, and flat warts)")

•Lichen striatus (picture 13A-E) (see "Lichen striatus")

•Linear verrucous epidermal nevus (picture 14)

•Linear Darier disease (see "Darier disease")

•Porokeratotic adnexal osteal nevus (a proposed term that incorporates porokeratotic eccrine ostial and dermal duct nevus [PEODDN] and porokeratotic eccrine and hair follicle nevus [PEHFN]) [116,117]

●Porokeratosis palmaris plantaris/punctate porokeratosis – Several other disorders may present with discrete, keratotic lesions on the palms and soles mimicking porokeratosis plantaris palmaris et disseminata (PPPD) and punctate porokeratosis. Examples include:

•Arsenical keratoses (picture 15)

•Palmoplantar keratodermas (see "Palmoplantar keratoderma")

•Palmar pits in basal cell nevus syndrome (picture 16) (see "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)")

MANAGEMENT

General approach — Education about sun protection and clinical surveillance for malignant transformation are sufficient for the management of most patients with porokeratosis. However, patients who are concerned about the appearance of lesions or those with symptomatic disease (eg, pruritic or painful lesions) may desire therapeutic intervention.

Options for the treatment of porokeratosis include topical pharmacologic therapy, destructive therapies, surgical excision, and oral retinoids. Since no randomized trials have evaluated therapies for porokeratosis and the available data are insufficient for definitive recommendations on treatment, the choice of therapy is primarily based on factors such as lesion size and number, lesion location, aesthetic considerations, treatment availability, and patient preference. Our approach is as follows:

●For patients who desire quick therapy for a few small lesions and who would not be disturbed by residual changes in skin pigmentation or scarring, destructive therapies, such as cryotherapy, curettage and electrodesiccation, photodynamic therapy, and laser therapy, or surgical excision can be offered.

●For patients with multiple or large lesions, topical pharmacologic therapy with topical fluorouracil or imiquimod can be offered. For older patients with widespread lesions, radiotherapy with Grenz rays may be a treatment option.

●For patients who do not desire intensive treatment, application of keratolytic agents, such as over-the-counter products containing urea or salicylic acid, may be beneficial.

The intense inflammatory response that typically accompanies treatment with topical fluorouracil or imiquimod limits the skin area that can be treated at one time. If treatment of a large area is required, topical retinoids, such as tretinoin or tazarotene, may be an alternative, although a longer treatment duration of several months is typically required.

The response to treatment with topical agents is often unpredictable, and clinicians must remain cognizant that lesions that initially respond well to any treatment can recur. Additional options for the treatment of porokeratosis include emollients and topical keratolytics (eg, salicylic acid). (See 'Topical therapies' below.)

Systemic retinoids are generally restricted to severe cases due to the possibility of systemic adverse effects and the high likelihood for lesion recurrence after the discontinuation of treatment. (See 'Surgical and destructive therapies' below and 'Systemic therapy' below.)

Sun protection — Due to the possibility for malignant transformation in porokeratosis, patients should be strongly encouraged to engage in protection from ultraviolet radiation, a known risk factor for squamous cell and basal cell carcinoma. (See 'Malignant transformation' above.)

We recommend sun-protective clothing, shelter from the sun, and routine daily use of broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30 on areas of skin that cannot be protected physically. Of note, strict use of sun protection may increase the risk for vitamin D deficiency, especially in patients with phototypes IV to VI. (See "Selection of sunscreen and sun-protective measures".)

Topical therapies

Overview — There are no randomized clinical trials assessing topical therapies of porokeratosis, and their use is largely based on indirect evidence from studies on treatment of actinic keratosis (see "Treatment of actinic keratosis"). The optimal treatment regimen/duration has not been determined, and the response to treatment is often unpredictable. Combination therapy using several different topical agents or topical agents and destructive therapies may be beneficial.

Topical therapeutic options for porokeratosis include:

●Topical fluorouracil – Topical fluorouracil has been used in patients with disseminated superficial actinic porokeratosis (DSAP), disseminated superficial porokeratosis (DSP), porokeratosis of Mibelli, and linear porokeratosis [48,118-121]. Patients are instructed to apply 5% topical fluorouracil cream daily until an intense inflammatory response is attained (typically several weeks). The intense inflammatory response with possible superficial ulceration and postinflammatory hyperpigmentation limits the use of fluorouracil to less esthetically important areas.

●Topical imiquimod – Topical imiquimod has been used in case reports and small case series of patients with porokeratosis of Mibelli, DSAP, linear porokeratosis, and porokeratosis plantaris palmaris et disseminata (PPPD) [122-132]. A systematic review found nine reports (11 patients) of partial to complete resolution of porokeratosis of Mibelli with imiquimod [118].

A reasonable initial course of therapy for imiquimod is application three to five times per week for a period of four to six weeks [123-125]. Longer or shorter periods of treatment may be needed depending on the treatment response and the occurrence of adverse effects [126,127]. Similar to topical fluorouracil, an intense local inflammatory response is expected during treatment with imiquimod.

●Topical retinoids – Tretinoin 0.05% cream and 0.1% gel have been beneficial for the treatment of linear porokeratosis [133-135]. Tazarotene and adapalene have also been used in some patients with porokeratosis [136]. Topical retinoids are applied once daily. They are less irritating and induce less inflammation than topical fluorouracil or imiquimod but require a longer course of treatment (10 to 16 weeks or longer) [133-135].

●Topical vitamin D analogs – Topical vitamin D analogs, such as calcipotriol and tacalcitol, have only been reported to be effective in DSAP, and several months or more of treatment with daily application may be required for improvement [4,137-139].

●Topical diclofenac – The value of topical diclofenac 3% gel is unclear. In a series of eight patients with DSAP, only one patient had partial improvement after six months of treatment [140]. In a single case report, topical diclofenac was effective in inducing partial resolution of inflammatory DSAP lesions that persisted despite treatment with systemic retinoids [57]. A small case series suggests that the drug may be effective in reducing disease progression [141].

●Topical statin-cholesterol – The combination of 2% simvastatin and 2% cholesterol cream was demonstrated to reduce lesion number, scaling, and erythema compared with emollient in an open-label study [142]. In this study, eight patients with DSAP were treated with simvastatin-cholesterol cream twice daily on one limb and emollients on the other. Simvastatin is believed to inhibit the production of toxic metabolites, while cholesterol is thought to restore the barrier function of the epidermis.

In a subsequent, small, randomized trial, 31 participants with DSAP were assigned to treatment with topical lovastatin 2% plus cholesterol 2% cream or lovastatin 2% cream once or twice daily [143]. At 12 weeks, a similar decrease from baseline in disease severity (assessed by the Disseminated Superficial Actinic Porokeratosis General Assessment Severity Index [DSAP-GASI]) was noted in both groups (from 3.08 points [95% CI 2.57-3.60] to 1.54 points [95% CI 1.04-2.05] and from 2.92 points [95% CI 2.40-3.43] to 1.50 points [95% CI 0.99-2.01], respectively).

Combination topical therapy — In the authors' experience, pretreatment of affected skin with a topical retinoid, such as tretinoin or tazarotene, for two to three weeks prior to the use of topical fluorouracil or imiquimod seems to improve drug penetration and the response to therapy. The relative efficacy of this regimen to treatment with topical fluorouracil or imiquimod alone has not been formally studied in porokeratosis. Other combinations described in a few case reports include adapalene with calcipotriol [136], imiquimod with fluorouracil [144], and topical fluorouracil cream with photodynamic therapy (PDT) [145].

Adjunctive topical therapies — The application of keratolytic agents, such as salicylic acid, may also be beneficial [146]. Successful treatment with salicylic acid in combination with fluorouracil or imiquimod has been reported [131,147]. In two patients with porokeratosis of Mibelli, lesion clearance was achieved with topical cantharidin [148].

Topical corticosteroids may provide symptomatic relief but only partial or no improvement of lesions [122]. There is a single report of successful use of topical tacrolimus for linear porokeratosis [149].

Emollients, especially with keratolytic properties (eg, urea-containing emollients), may be useful in patients with porokeratosis, as they may reduce the rough, dry quality of lesions.

Surgical and destructive therapies — Porokeratosis lesions can be removed or improved with procedures such as cryotherapy, curettage and electrodesiccation, surgical excision, and dermabrasion [150-154]. However, all of these treatments are associated with a high risk of scarring or postinflammatory hyperpigmentation. Alternative approaches include:

●Laser therapy – Light-based therapies may also be effective. Carbon dioxide laser has been successfully used to treat porokeratosis of Mibelli and linear porokeratosis [155-158]. Improvement in DSAP or DSP has been reported after treatment with a fractional laser, Q-switched ruby laser, frequency-doubled neodymium:yttrium aluminum garnet (Nd:YAG) laser, and erbium:yttrium aluminium garnet (Er:YAG) laser [159-163]. Combination of carbon dioxide laser and conventional methyl aminolevulinate-PDT showed improvement of the condition but no complete resolution of DSAP lesions [164]. (See "Photodynamic therapy".)

●Photodynamic therapy – Case reports of conventional PDT in DSAP and linear porokeratosis have yielded variable results [145,165-168]. Daylight PDT has led to favorable results in four patients with DSAP [169,170]. (See "Photodynamic therapy", section on 'Daylight photodynamic therapy'.)

●Radiation therapy – In a report of eight patients with DSAP, radiotherapy with Grenz and soft rays resulted in a good response in all patients, with only one recurrence suspected (picture 17) [171]. An inflammatory reaction and postinflammatory hyperpigmentation occurred in some cases and resolved spontaneously in several months. Another case series reported 17 patients successfully treated with Grenz rays, with at least 50 percent improvement in all cases [172].

Systemic therapy — Oral retinoids, including acitretin and isotretinoin, are infrequently used for the treatment of severe cases of porokeratosis. Retinoids have been reported to be effective in patients with DSAP, linear porokeratosis, porokeratosis of Mibelli, PPPD, and generalized linear lesions [73,173-176]. However, systemic retinoids need to be administered for many months. The degree of improvement is variable; recurrence after treatment discontinuation is likely. Systemic retinoids are teratogenic. Acitretin is contraindicated in female patients of childbearing potential; pregnancy must be avoided for three years after discontinuation.

In a single case report, a patient with DSAP who received the keratinocyte differentiation factor palifermin for mucositis prophylaxis under chemotherapy for solid tumor treatment showed a marked improvement of DSAP with sustained clearance of the lesions at 12 months follow-up [177].

SKIN CANCER PREVENTION AND SURVEILLANCE

General principles — Although removal of lesions via surgical or destructive methods is an option for the prevention of malignant transformation in lesions of porokeratosis, this is generally not needed or feasible, especially for patients with large or extensive lesions. Factors, such as the estimated risk for malignancy for specific lesion types and the risk for significant cosmetic or functional defects following removal, must be considered. The removal of the lesions with the greatest risk for malignancy (linear porokeratosis or large porokeratosis of Mibelli) often would result in an unacceptable amount of scarring and, possibly, functional impairment.

Clinical surveillance with regular skin examinations and patient education about the warning signs of skin cancer and sun protection are thus key aspects of the management of patients with major types of porokeratosis. Although malignant transformation in DSAP and DSP is rare compared with porokeratosis of Mibelli and linear porokeratosis, the frequent presence of additional risk factors for cutaneous malignancy (eg, light skin type, history of high sun exposure, immunosuppression) makes close clinical follow-up of these patients worthwhile:

●Patient education – All patients should be educated about warning signs for malignancy. Patients should be instructed to return for follow-up if changes occur in a previously stable lesion, such as the development of induration, ulceration, nodularity, bleeding, crusting, or rapid growth. Similarly, patients should return for reevaluation if new symptoms develop in lesions (eg, prickling or tingling sensations or pain).

●Sun protection – The implementation of sun-protective practices is recommended to reduce actinic damage. (See 'Sun protection' above and "Selection of sunscreen and sun-protective measures".)

●Routine follow-up – Patients should be followed annually to monitor for signs and symptoms of malignancy, to screen for changes in health status that might suggest an underlying systemic immunosuppressive disorder, and to reinforce sun protection education. In case of high number or large lesions, more frequent follow-up visits (eg, every six months) should be scheduled. Any lesion that exhibits clinical features suspicious for malignancy (eg, induration, ulceration, bleeding, crusting, rapid growth) should be excised or biopsied for histopathologic examination.

If the decision is made to excise or destroy a lesion for prophylactic purposes, doing so in an urgent manner is not necessary, as the period between lesion development and malignancy often spans decades (see 'Malignant transformation' above). After removal, clinical follow-up still should be performed yearly to evaluate these patients for the development of new or recurrent lesions.

Immunocompromised patients — Although systemic immunosuppression has not been proven to increase the risk for malignant transformation in lesions of porokeratosis [36,101], immunosuppression is a known risk factor for cutaneous malignancy. Thus, skin examinations are often performed more than once yearly for skin cancer surveillance in this population regardless of the presence or absence of porokeratosis. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Follow-up'.)

Chemoprevention — Systemic retinoids are occasionally used for the management of patients with severe porokeratosis. Based on indirect evidence from studies on chemoprevention of cutaneous squamous cell carcinoma in solid organ transplant recipients, the risk for malignant transformation may be reduced during active treatment with systemic retinoids [178]. However, this has not been directly studied in porokeratosis, and the long-term impact of retinoid therapy on malignant transformation of these lesions is unknown.

In a randomized trial, daily use of 1000 mg of nicotinamide for 12 months reduced the number of new basal cell carcinoma and squamous cell carcinoma by 20 and 30 percent, respectively, in patients at high risk of nonmelanoma skin cancer [179]. However, the value of nicotinamide supplementation in the prevention of skin cancer in patients with porokeratosis has not been specifically studied. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Chemoprevention for squamous cell carcinoma' and "Cutaneous squamous cell carcinoma: Primary and secondary prevention", section on 'Chemoprevention'.)

PROGNOSIS — Without treatment, lesions of porokeratosis usually persist indefinitely [98]. Spontaneous regression is rare [36].

Malignant transformation is estimated to occur in 7 to 11 percent of patients with porokeratosis, most often in lesions of linear porokeratosis or giant porokeratosis (a form of porokeratosis of Mibelli). The vast majority of squamous cell carcinomas that develop in lesions of porokeratosis are successfully treated with local therapy. However, several cases of metastatic squamous cell carcinoma arising in the setting of porokeratosis have been reported [101,180-183]. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)" and "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma".)

SUMMARY AND RECOMMENDATIONS

●Definition and classification – Porokeratosis is a rare, sporadic or inherited disorder of keratinization characterized by the presence of a characteristic ridge-like, keratotic border called a "cornoid lamella" (picture 1B). Several clinical variants of porokeratosis, of which the most common are disseminated superficial actinic porokeratosis (DSAP) and porokeratosis of Mibelli, have been described. (See 'Introduction' above and 'Classification' above.)

●Clinical features – The defining feature of porokeratosis is the clinical and histopathologic presence of a cornoid lamella, which typically manifests as a thin, keratotic rim at the periphery of a slightly atrophic skin lesion of variable size (picture 1A-B). Lesions typically begin as small, keratotic papules that spread slowly and centrifugally:

•Disseminated superficial actinic porokeratosis – DSAP is the most common form of porokeratosis. Patients are typically adults with a history of chronic sun exposure. Few or many small, porokeratotic macules are usually present on the extensor extremities (picture 1B, 2B). (See 'Disseminated superficial actinic porokeratosis' above.)

•Porokeratosis of Mibelli – Porokeratosis of Mibelli is the second most common type of porokeratosis. Lesions most commonly begin in childhood but may occur in adults, particularly in the setting of immunosuppression. An annular plaque a few centimeters in diameter with a prominent keratotic ridge is the typical clinical finding (picture 1A, 1C, 1E). (See 'Porokeratosis of Mibelli' above.)

●Risk of squamous cell carcinoma – Malignant transformation to squamous cell carcinoma is estimated to occur in 7 to 11 percent of patients with porokeratosis, most often in lesions of linear porokeratosis or giant porokeratosis (a form of porokeratosis of Mibelli). (See 'Malignant transformation' above.)

●Diagnosis – Clinical examination is usually sufficient for the diagnosis of porokeratosis. Skin biopsy may be useful in the setting of atypical lesions or lesions that are suspicious for malignant transformation. Biopsy of the periphery of the lesion characteristically demonstrates a cornoid lamella, consisting of a narrow column of parakeratotic cells (picture 7A). (See 'Diagnosis' above and 'Histopathology' above.)

●Management – Education about sun protection and clinical surveillance for malignant transformation are sufficient for the management of most patients with porokeratosis. However, patients with symptomatic or cosmetically distressing lesions may desire treatment (see 'General approach' above):

•Patients with few small lesions – For patients with a few small lesions who desire rapid treatment for symptom relief or cosmetic purposes, we suggest treatment with destructive therapies (eg, cryotherapy, curettage and electrodesiccation, laser therapy) or surgical excision (Grade 2C). Treatment-related pigmentation changes or scarring may occur. (See 'Surgical and destructive therapies' above.)

•Patients with large or multiple lesions – For patients with large or multiple lesions that are not amenable to surgical or destructive therapy, we suggest treatment with topical therapies rather than systemic therapy (Grade 2C). Topical fluorouracil or imiquimod may be used for the treatment of localized areas. Topical retinoids are a less irritating therapeutic option and, thus, suitable for use on larger areas but may require a longer course of therapy. (See 'Topical therapies' above.)

Sequential therapy with topical retinoids for two to three weeks followed by a course of topical fluorouracil or imiquimod may enhance drug penetration and response to treatment (see 'Combination topical therapy' above). Treatment with systemic retinoids is usually reserved for severe cases. Relapse is likely after treatment cessation. (See 'Systemic therapy' above.)

●Skin cancer prevention and surveillance – Clinical surveillance with annual skin examinations and patient education about the warning signs of skin cancer and sun protection are key aspects of the management of patients with major types of porokeratosis. (See 'Skin cancer prevention and surveillance' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Linda V Spencer, MD, who contributed to an earlier version of this topic review.