Porokeratosis is a clonal disorder of keratinization characterized by one or more atrophic patches surrounded by a clinically and histologically distinctive hyperkeratotic ridgelike border called the cornoid lamella. Multiple clinical variants of porokeratosis are recognized. Malignancies, typically squamous cell carcinomas, may develop within lesions of porokeratosis.
The most common forms of porokeratosis are as follows:
A patient may develop more than one type of porokeratosis simultaneously or consecutively.
Less commonly reported clinical entities that share the histopathologic characteristic of cornoid lamellation include the following:
Clonal proliferation of atypical keratinocytes showing abnormal terminal keratinocyte differentiation leads to the formation of the cornoid lamella. This expands peripherally and forms the raised boundary between abnormal and normal keratinocytes. The atypical keratinocytes show abnormal differentiation but do not show an increased rate of proliferation.[8, 9]
It is not known what triggers this process, and more than one causative factor may be involved. Several risk factors for the development of porokeratosis have been identified, including genetic inheritance, ultraviolet radiation, and immunosuppression.
Inherited or sporadic genetic defects, possibly creating a change in immune function and/or keratinocyte function, are thought to be responsible for several forms of porokeratosis. Familial cases of all forms of porokeratosis have been reported and appear to have an autosomal dominant inheritance pattern with incomplete penetrance. Several chromosomal loci have been identified for DSAP, DSP, and PPPD.[10, 11, 12, 13, 14, 15, 16] The focal variants of porokeratosis (PM and linear porokeratosis) may occur through mosaicism, in which somatic mutations cause focal loss of heterozygosity. Genetic mutations in the SART3 and MVK genes have been found in DSAP pedigrees.
Natural or artificial ultraviolet radiation, electron beam therapy, and extensive radiation therapy are well-established trigger factors for DSAP and PM. Sun exposure in genetically susceptible individuals is thought to cause DSAP, although the sparing of facial skin in most patients is unexplained.
Immunosuppression associated with porokeratosis may be secondary to a disease process or medications. Diseases reported in association with porokeratosis include HIV infection, diabetes mellitus, liver disease, and hematologic or solid organ malignancy.[21, 22] Immunomodulating drugs used to treat autoimmune diseases or to prevent organ transplant rejection may also trigger porokeratosis.[23, 24, 25, 26, 27, 28, 29, 30, 31] Localized cutaneous immunosuppression due to long-term application of a potent topical steroid was reported to induce PM. The incidence of porokeratosis in organ transplant recipients has been reported to be anywhere from 1-11%[24, 27]
Immunosuppression may induce new lesions or cause preexisting lesions to flare. New lesions of porokeratosis have occurred as quickly as 4 months after initiation of immunosuppressive therapy, or as long as 14 years[27, 29] and may resolve following cessation of immunosuppressive therapy.[30, 31]
Trauma, such as a burn, may also trigger porokeratosis.
DSAP and PM are the most commonly seen variants. The other forms of porokeratosis are rare.
Porokeratosis most commonly occurs in fair-skinned individuals. Porokeratosis is rare in darker-skinned populations.
PM and PPPD affect men twice as often as women.
DSAP is twice as likely to develop in women compared with men.
Linear porokeratosis is seen with equal incidence in men and women.
PPPD and linear porokeratosis may be seen at any age, from birth to adulthood.
PM usually develops in childhood.
Disseminated superficial porokeratosis (DSP) generally develops in the third or fourth decade of life.
Porokeratosis of Mibelli is the second most common form of porokeratosis, accounting for about a third of reported cases. It is seen in men more than twice as often as women and may first appear in childhood or young adulthood. PM initially appears as a small, asymptomatic, or slightly pruritic lesion develops that slowly expands over a period of years. Less commonly, lesions may develop during adulthood and enlarge rapidly, usually in the clinical setting of immunosuppression. Occasionally, patients have a history of an antecedent trauma, such as a burn wound.
Most PM lesions reach several centimeters in diameter, although “giant porokeratosis” lesions might grow to 10 cm or 20 cm. Classically, PM lesions are located on an extremities, although they may occur anywhere, including the palms, soles, genitalia, or mucous membranes.[34, 36, 37] The center of the lesion may be slightly hypopigmented or hyperpigmented, minimally scaly, slightly atrophic, and hairless. Occasionally lesions may be confluent thick hyperkeratotic or verrucous plaques.[38, 39]
Disseminated superficial (actinic) porokeratosis is the most common form of porokeratosis, and may account for almost half of all cases. Patients develop a few to several dozen tan, annular macules with raised peripheral ridges, developing predominantly on the distal extensor surfaces of the legs and the arms. Palms and soles are spared, and facial lesions may be seen in less than 15% of patients. Hyperkeratotic variants have been described. The lesions are usually asymptomatic, but they may itch or sting slightly. Extensive exposure to natural or artificial ultraviolet radiation may trigger or worsen DSAP.
The cornoid lamellae may be stained and accentuated by sunless tanning lotions containing dihydroxyacetone.
Patients are typically women in their third or fourth decade of life, with a history of ultraviolet light exposure. Patients may have a history of phototherapy for psoriasis. There is frequently a family history of DSAP, especially in other females in the family.
Lesions of disseminated superficial porokeratosis (non-actinic) appear very similar except in a generalized distribution. Patients with DSP may be more likely to be immunosuppressed and to be less likely to have worsening with sun exposure than patients with DSAP.
Linear porokeratosis lesions typically develop during infancy or early childhood and may represent a segmental form of DSP.[42, 17] Females are slightly more likely to be affected than males. Lesions arise usually as unilateral reddish brown patches or linear keratotic papules and plaques that are typically distributed along Blaschko's lines, suggesting cutaneous mosaicism. Less commonly patients may have bilateral involvement with a generalized or systematized forms.
All cases of linear porokeratosis have a higher risk of malignant degeneration than other forms of porokeratosis, possibly because of the allelic loss hypothesized to be at fault for the formation of the lesions.
Small, relatively uniform lesions first develop in adolescence or early adulthood on the palms and the soles. They may then spread in a more generalized distribution, occasionally along lines of Blaschko. The lesions are usually asymptomatic, but they may itch or be tender to palpation and plantar lesions may cause discomfort with walking. Disseminated areas of involvement may include the mucosal membranes, where they occur as multiple small, depressed, opalescent rings with hyperemic borders. Males are affected twice as often as females.
Punctate porokeratosis presents as multiple, asymptomatic, tiny, hyperkeratotic papules with thin, raised margins developing on the palms and the soles during adulthood. Some authors consider this to be a forme fruste of PPPD, rather than a separate entity.
Porokeratosis ptychotropica presents with inflammatory keratotic plaques with histopathologic foci of cornoid lamellae on the buttocks or genitals, and may be mistaken for psoriasis.[45, 46]
Follicular porokeratosis is described as an eruptive papular porokeratosis in the setting of DSP. Porokeratosis may occur syndromically with craniosynostosis and anal anomalies (CAP syndrome).
Porokeratotic adnexal osteal nevus is the name proposed to incorporate porokeratotic eccrine ostial and dermal duct nevus (PEODDN) and porokeratotic eccrine and hair follicle nevus (PEHFN). It is considered a congenital lesion, usually developing during infancy or childhood. Lesions consist of hyperkeratotic papules and plaques, and occasionally punctate pits filled with a comedolike keratin plug. It develops typically on the distal extremities, although proximal extremities, trunk, and face may be involved. During the neonatal period, the lesions may initially appear as erosions. Lesions are often aligned along Blaschko's lines and may extend into nailbeds. See the image below.
A young boy with a linear lesion of porokeratotic eccrine ostial and dermal duct nevus extending onto the nailbed, causing pterygium formation.
The lesion develops as a small, light brown, keratotic papule that slowly expands to form an irregularly shaped, annular plaque with a raised, ridgelike border. This border may be hypertrophic or verrucous and may be greater than 1 mm in height. A thin furrow is typically seen in the center of the ridge, causing a Great Wall of China effect. The lesion is slightly hypopigmented or hyperpigmented, minimally scaly, slightly atrophic, hairless, and anhidrotic. The size may vary from a few millimeters to several centimeters.
Lesions may be found anywhere, including the mucous membranes, although they most commonly occur on the extremities. Generally, few lesions are observed. Porokeratosis ptychotropica is a verrucous variant that is localized to the buttocks and clinically resembles psoriasis. Note the image below.
Porokeratosis of Mibelli on the lower leg in a renal transplant recipient.
Dozens of small, indistinct, light brown patches with a threadlike border are seen on the extensor surfaces of the arms and the legs.
Facial lesions are seen in approximately 15% of patients. Nonactinic DSP has a generalized distribution, sparing the palms and the soles. Bullous and pruritic variants have been described. Note the images below.
Disseminated superficial actinic porokeratosis on the lower legs of a female patient.
A 42-year-old woman with multiple lesions on the pretibial aspects of the legs.
Grouped, linearly arranged, annular papules and plaques with the characteristic raised peripheral ridge are seen unilaterally on an extremity, the trunk, and/or the head and neck area. The lesions commonly follow a dermatomal or blaschkoid distribution, and they may arise initially as reddish-brown patches.
Multiple linear groups may be seen in one patient. They may be seen in association with other forms of porokeratosis. Individual lesions within the linear grouping have a well-developed border, often with a central furrow similar to that seen in classic PM.
Clinical changes consistent with the development of a basal or squamous cell carcinoma are more common in linear porokeratosis than in other forms of porokeratosis.
The lesions are small, superficial, relatively uniform, with a slightly hyperpigmented, atrophic center and a minimally raised peripheral ridge. Mucosal lesions are small, annular or serpiginous, and pale. Squamous cell carcinoma has been reported to develop within lesions of PPPD.
Dozens of discrete or grouped seedlike hyperkeratotic lesions with characteristic thin, raised ridgelike margins develop on the palms and the soles. Patients usually have other forms of porokeratosis as well, most commonly the linear or Mibelli types. Punctate porokeratosis may be clinically and histologically indistinguishable from punctate porokeratotic keratoderma, which is considered to be a cutaneous sign of an internal malignancy.
Porokeratosis ptychotropica presents with multiple plaques involving the medial buttocks and gluteal cleft, clinically resembling psoriasis.
Patients with porokeratotic adnexal ostial nevus develop hyperkeratotic papules and plaques, and occasionally punctate pits filled with a comedolike keratin plug. The lesions are typically on the extremities and occasionally the trunk and/or face. If present at birth, they may present as erosions that evolve into darker brown, well-marginated linear plaques. Pterygium formation can occur if lesions extend into the nail bed. Lesions are often distributed along the lines of Blaschko.
Rare case reports of PAON describe other findings, including psoriasis, focal anhidrosis, developmental delay, seizures, scoliosis, hemiparesis, polyneuropathy, hyperthyroidism, hearing loss, and breast hypoplasia. Squamous cell carcinoma has been reported to develop within well-established lesions. Additionally, late-onset lesions developing during adulthood may be clinically indistinguishable from PPPD.
Risk factors for porokeratosis include genetic inheritance, ultraviolet light exposure, and immunosuppression. One study found that approximately 10% of patients who had undergone renal transplantation developed porokeratosis.
Autosomal dominant inheritance and immunosuppression are the usual causes. PM has been seen following radiation therapy, at burn wounds, and at hemodialysis sites.
Sun exposure and/or artificial ultraviolet radiation exposure in a patient who is genetically predisposed causes DSAP. Exacerbations have been reported following prolonged sun exposure, repeated tanning bed exposure, electron beam radiation therapy, and therapeutic phototherapy or photochemotherapy for psoriasis. Drug-induced photosensitivity may play a role. Protection from ultraviolet radiation may lead to spontaneous resolution. Additionally, immunosuppression predisposes patients to both DSAP and nonactinic DSP.
No definite inheritance pattern has been established. Loss of heterozygosity has been proposed as a genetic mechanism and may explain the higher risk of malignant degeneration seen in linear porokeratosis in comparison to other forms of porokeratosis.
Familial PPPD is transmitted in an autosomal dominant mode with variable penetrance. Acquired PPPD may be caused by immunosuppression, or it may be a cutaneous marker of internal malignancy.
This condition has no unique inheritance pattern and is usually associated with other forms of porokeratosis.
Generally, no laboratory studies are required. Screening for diseases causing immunosuppression (eg, HIV, hematologic malignancies) and/or renal failure is appropriate when new lesions of classic porokeratosis of Mibelli (PM) or disseminated superficial porokeratosis (DSP) are seen or when sudden exacerbation of any form of porokeratosis develops.
The cornoid lamella is the histopathologic hallmark of all forms of porokeratosis. It is essential that a biopsy specimen be taken from the peripheral, raised, hyperkeratotic ridge to demonstrate this finding.
The cornoid lamella consists of a thin column of tightly packed parakeratotic cells within a keratin-filled epidermal invagination. The parakeratotic column extends at an angle away from the center of the lesion and develops from the interfollicular epidermis, but it may involve the ostia of hair follicles or sweat ducts. Within the parakeratotic column, the horny cells appear homogeneous and possess deeply basophilic pyknotic nuclei. In the epidermis beneath the parakeratotic column, the keratinocytes are irregularly arranged and have pyknotic nuclei with perinuclear edema. No granular layer is seen within the parakeratotic column, while the keratin-filled invagination of the epidermis has a well-developed granular layer.
The papillary dermis beneath the cornoid lamella contains a moderately dense, lymphocytic infiltrate and dilated capillaries. Dermal amyloid deposits have been described in some cases of disseminated superficial actinic porokeratosis (DSAP). They have also been described in the intertriginous portion of porokeratosis ptychotropica, suggesting a role for friction in pathogenesis of this variant of PM.
Specimens taken from the center of the lesion show atrophy, with areas of liquefaction degeneration in the basal layer, colloid-body formation, and flattening of rete ridges. The dermis may be edematous or fibrotic with telangiectasia. Amyloid deposition may be seen in the papillary dermis, both centrally and beneath the cornoid lamellae. The cornoid lamella is prominent in PM but less distinct in DSAP, DSP, and porokeratosis palmaris et plantaris disseminata (PPPD). At the ultrastructural level, vacuolization of keratinocytes, clumping of keratin filaments, and a paucity of lamellar bodies are found. Intercellular lamellar sheets are incompletely formed and may be responsible for defective desquamation.
Immunohistochemical studies show that keratinocytes beneath the cornoid lamella stain in a pattern similar to that observed in squamous cell carcinomas. The parakeratosis appears to be the result of faulty maturation of keratinocytes, rather than an increased rate of proliferation. Keratinocytes central to the cornoid lamella stain in a pattern identical to that of premalignant lesions, such as actinic keratosis. Keratinocytes peripheral to the cornoid lamella stain normally.
Recent studies showing reduced bleomycin hydralase expression in porokeratosis lesions support the hypothesis that the pathogenesis of porokeratosis involves a defect in the late stage of epidermal differentiation.
The approach to treatment must be individualized, based on the size of the lesion and the anatomical location, the functional and aesthetic considerations, the risk of malignancy, and the patient's preference. Protection from the sun, use of emollients, and watchful observation for signs of malignant degeneration may be all that is needed for many patients. If lesions are widespread and medical treatment is desired, several medications have potential benefit.
Topical 5-fluorouracil can induce remission in all forms of porokeratosis.[51, 52] Treatment must be continued until a brisk inflammatory reaction is obtained. Enhancement of penetration, which heightens the response, may be achieved by occlusion or the addition of topical tretinoin, tazarotene, or salicylic acid. Recurrences may be seen.
Both calcipotriol and tacalcitol have been shown to be effective after 3-6 months of treatment of disseminated superficial actinic porokeratosis (DSAP).[54, 55, 56]
Topical imiquimod cream has been shown to be effective for treating classic porokeratosis of Mibelli (PM).[57, 58]
Topically applied retinoids (tretinoin, tazarotene) may be beneficial for improving the abnormality in keratinization that causes cornoid lamellation, thereby reducing the hyperkeratosis of the edge of the lesions. It is also thought to improve the percutaneous absorption of other topically applied medications, rendering them somewhat more effective.
Diclofenac gel 3% (Solaraze), may be effective for DSAP.
The use of oral retinoids (isotretinoin, etretinate, and acitretin) in patients who are immunosuppressed, who are at higher risk for malignant degeneration, may reduce the risk of carcinoma in porokeratotic lesions.
Oral isotretinoin at 20 mg daily combined with topical 5-fluorouracil is reported to be effective for DSAP and porokeratosis palmaris et plantaris disseminata (PPPD), but it causes burning, itching, and painful erosions.
Prior to the removal of etretinate from the US market, conflicting reports of etretinate efficacy were published. Reports of etretinate efficacy are conflicting. Etretinate at doses of 75 mg/d for 1 week followed by 50 mg/d was shown to be helpful in linear porokeratosis and symptomatic PM. Higher doses of 1 mg/kg/d were reported to exacerbate lesions of DSAP after 4-6 weeks of treatment. Even when etretinate therapy is successful, relapses may occur. Digitate keratoses were reported to develop after the use of etretinate for DSAP.
Acitretin, a second-generation monoaromatic retinoid that is the active metabolite of etretinate, is likely to have results similar to those of etretinate. A case of systematized linear porokeratosis with good response to acitretin has been reported.[62, 63]
Surgical treatment is essential for porokeratosis lesions that have undergone malignant transformation. No studies showing the value of prophylactic nonexcisional surgical treatment in reducing the incidence of malignancy within porokeratosis have been reported. Surgical modalities other than excision may improve cosmesis and/or function but are frequently followed by relapses.
Excision is most appropriate when malignant degeneration develops.
Cryotherapy is helpful for porokeratosis lesions with minimally raised cornoid lamellae, such as DSAP and PPPD. It is a minimally invasive method of inducing resolution for large numbers of lesions.
Electrodesiccation and curettage can be used to treat small lesions or when cryosurgery is ineffective.
Diamond fraise dermabrasion has been used with conflicting reports of efficacy. It was effective in improving the appearance of linear porokeratosis in one patient, but a child with a large PM lesion had recurrence after treatment.
Various types of laser therapy have been used. A rapid recurrence reportedly followed carbon dioxide laser ablation. The 585 nm flashlamp-pumped pulsed dye laser was shown to help one patient with linear porokeratosis. Another patient with PM with an underlying hemangioma had good improvement of the hemangioma but no change in the porokeratosis after treatment. The frequency-doubled Nd:YAG laser was shown to be helpful for one patient with disseminated superficial porokeratosis (DSP). The Q-switched ruby laser has been reported to be effective in the treatment of DSAP and PM.[65, 66]
Ultrasonic surgical aspiration was shown to be effective in the treatment of vulvar porokeratosis in one patient.
Photodynamic therapy with methyl aminolevulinate has been reported to be successful for DSAP and linear porokeratosis.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Topically applied agents that might yield improvement in some patients include topical 5-fluorouracil, topical vitamin D-3 analogues, topical immunomodulators (imiquimod), and topical retinoids.
Clinical Context: Fluorouracil is preferentially taken up by cells that are dividing abnormally and rapidly; it interferes with DNA and RNA synthesis and leads to death of the abnormal cells. Fluorouracil 5% cream is most commonly used.; 1% cream may be used in thin-skinned areas.
These agents inhibit cell growth and proliferation.
Clinical Context: Calcipotriene cream 0.005% is a synthetic vitamin D-3 analog that regulates skin cell production and development. It is approved for the treatment of psoriasis and has been reported to be helpful in DSAP.
These agents regulate calcium-induced keratinocyte differentiation. Tacalcitol has been used, but it is not available in the United States.
Clinical Context: Tretinoin topical inhibits microcomedo formation and eliminates lesions. It makes keratinocytes in sebaceous follicles less adherent and easier to remove. It is used primarily to treat acne but has beneficial effects on actinic keratoses and may reduce the malignant potential of porokeratosis. Tretinoin topical is available as 0.025%, 0.05%, and 0.1% creams and 0.01% and 0.025% gels.
Clinical Context: Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of naturally occurring tretinoin (trans-retinoic acid). Both agents are structurally related to vitamin A. Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization. It treats severe recalcitrant cystic acne and appears to help in the treatment of porokeratosis.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.
Clinical Context: Acitretin is a second-generation monoaromatic retinoid and active metabolite of etretinate. It has demonstrated clinical effects close to those seen with etretinate. Its mechanism of action is unknown. No studies have looked at its effect on porokeratosis.
These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. They modulate keratinocyte differentiation and have been shown to reduce the risk of skin cancer formation in patients who have undergone renal transplantation.
Clinical Context: Imiquimod induces the secretion of interferon-alpha and other cytokines; its mechanism of action is unknown.
These agents modulate processes that promote immune reactions resulting from diverse stimuli.
Clinical Context: This is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Diclofenac gel 3% may be effective for DSAP.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are most commonly used for relief of mild to moderately severe pain. Although the pain-relieving effects tend to be patient-specific, ibuprofen is usually used for initial therapy.
Regularly monitoring patients for the development of malignant transformation is essential, especially in the setting of immunosuppression. Squamous cell or basal cell carcinomas can be aggressive in patients who are immunosuppressed.
Inpatient care is rarely necessary.
The most important complication to watch for is the development of cutaneous malignancy. Functional impairment due to involvement of critical anatomical locations may develop. Prophylactic excision could be considered in appropriate situations.
The prognosis is generally excellent. This is especially true for disseminated superficial porokeratosis (DSP).
Large lesions of porokeratosis, linear porokeratosis, or porokeratosis in an immunocompromised patients should be monitored carefully for the development of cutaneous malignancies within the porokeratosis lesions. These cutaneous malignancies often behave aggressively, with the potential for extensive local tissue destruction (basal cell carcinoma) and distant metastasis (squamous cell carcinoma). The formation of squamous cell carcinomas or, less commonly, basal cell carcinomas has been reported in all forms of porokeratosis.[68, 69, 70] Lesions that are large, long-standing, or linear have the greatest risk of developing an associated malignancy. Chromosomal instability and reduced immune surveillance with overexpression of p53 are hypothesized to play a role in the development of cutaneous malignancies within porokeratosis.[72, 73, 74, 75, 76]
PM circumferentially involving the digits may induce pseudoainhum. Most lesions are asymptomatic. Ulcerative lesions have been described. Giant PM in a facial or acral location may cause destruction of underlying soft tissue or pseudoainhum with amputation.
Very rarely, porokeratosis-associated squamous cell carcinomas may metastasize and cause death.[78, 79]
Patients must practice strict sun precautions. These measures include wearing protective clothing; applying sunblock; avoiding exposure to midday sunlight; and discontinuing exposure to artificial ultraviolet light, such as tanning beds and therapeutic phototherapy.
Consideration for vitamin D3 supplementation should be made given the need for careful sun avoidance and protection.
Patients must periodically examine their skin for lesions suggestive of malignancy. A qualified physician should promptly evaluate any change in a porokeratosis lesion.
Family members should be examined for porokeratosis if familial porokeratosis is suspected.