Patient Presentation
A 57-year-old African-American woman presented with violaceous-brown annular plaques and papules with knife-like, double-edge, hyperkeratotic rims on her bilateral thighs and right pretibial areas. (See image above.) These lesions were asymptomatic and gradually appeared over 4 months. The patient’s past medical history was pertinent for systemic sarcoidosis and IgG Kappa monoclonal gammopathy. She denied medication changes within the past 6 months. Her social and family histories were unremarkable. A skin biopsy was performed to determine the diagnosis.
What’s Your Diagnosis?
Diagnosis: Disseminated Superficial Actinic Porokeratosis (DSAP)
Porokeratosis, an epidermal keratinization disorder, is characterized by its unique appearance of hyperkeratotic papules and plaques with double-edged borders. It has six clinical variants, which include porokeratosis of Mibelli, disseminated superficial actinic porokeratosis (DSAP), linear porokeratosis (LP), porokeratosis palmaris et plantaris disseminata (PPPD), porokeratosis punctata palmaris et plantaris (PPPP), and disseminated superficial porokeratosis (DSP). (See Table 1.)
Classical porokeratosis of Mibelli is described as large annular plaques with normal or atrophic centers enclosed by a hyperkeratotic border.1,2,3 Mibelli first described this classic form in 1893 and coined the term “porokeratosis,”4 while Respighi described the disseminated superficial form (DSP).5 Guss et al acknowledged PPPD in 1971,6 while PPPP was designated as a minor type of porokeratosis in 1977.7
DSAP — Most Common Form
Our patient’s skin eruption is the most common form of porokeratosis, DSAP,2 which was first described by Chernosky in 1966.8 Clinical presentation of DSAP usually occurs in the third to fourth decade of life with a greater incidence in women.1 DSAP is most commonly seen in Caucasians with a history of significant sun exposure.9 Although our patient was an African-American female, she did report history of significant sun exposure.
Other Variants
There are other extremely rare variants of porokeratosis that do not fall into the six main subtypes including giant, hyperkeratotic, reticulated, genital and zosteriform.10 Coexistence of different variants of porokeratosis is also fairly uncommon, although cases of linear porokeratosis have been described with DSAP.11,12 Congenital cases are even rarer, yet a 5-year-old girl born with linear porokeratosis who developed DSP at the age of 3 has been noted.13 Recent reports in literature of coexisting porokeratosis with multiple squamous cell carcinomas have also been described.10
Clinical Features
Porokeratosis is usually an asymptomatic skin disorder of benign epidermal proliferation,14 which can be divided into localized and disseminated variants with different clinical presentations. Localized types consist of the classic porokeratosis of Mibelli, LP, and PPPP; disseminated variants consist of DSP, DSAP and PPPD.8,15,16
In terms of the disseminated variants, DSAP presents in middle-aged to elderly patients with many small (0.1 to 0.3 cm in diameter), annular, anhidrotic, and keratotic papules and plaques with slightly elevated hyperkeratotic rims and minimally atrophic centers.1,17,18 Skin lesions of DSAP characteristically affect sun-exposed areas — particularly lower extremities — and an earlier onset of DSAP may be associated with increased exposure to sunlight.19 Conversely, DSP is characterized by small, brown annular lesions with an elevated hyperkeratotic ridge mainly on the extremities in a bilateral, symmetric fashion; its usual age of onset is before age 20.1,3 PPPD is illustrated by keratotic red to brown papules that are initially localized superficially to the palms and soles both bilaterally and symmetrically, but which over a period of several months to years, disseminate throughout the body.1,20,21
The most prominent localized variant of porokeratosis is the classic porokeratosis of Mibelli, which typically first appears during childhood and is described as small asymptomatic keratotic papules or larger plaques with the classic hyperkeratotic ridge that are most commonly unilateral and localized on the extremities.9
Linear porokeratosis, characterized by small keratotic papules with hyperkeratotic borders in linear configuration,3 has an earlier age of onset, affecting children under the age of 10 with congenital cases also reported.22 Linear porokeratosis is more commonly seen as unilateral lesions on distal extremities; however, on very rare occasions, it can present bilaterally on all extremities as well as the trunk.1,16
Exhibiting punctate, keratotic, often spine-like lesions, PPPP lesions are confined to a patient’s palms and soles.9,23
Histology
Porokeratosis is histologically characterized by the presence of a cornoid lamella, a thin column of parakeratotic cells extending through the stratum corneum with loss of granular layers.24 In order to visualize the typical cornoid lamella, the biopsy must be obtained of the raised, peripheral, hyperkeratotic rim.25 Within the parakeratotic column of the cornoid lamella, the horny cells appear homogenous with pyknotic nuclei; the epidermis below this column contains irregularly arranged keratinocytes, with pyknotic nuclei and perinuclear edema. Due to premature keratinization, some cells in the upper stratum malpighii have an eosinophilic cytoplasm, as well. Electron microscopy also shows keratinocyte degeneration in the epidermis below the parakeratotic column.25
The cornoid lamella represents a localized area of faulty keratinization that is regarded as a clonal disease.24 This ridge will show a keratin-filled invagination of the dermis.25 A PAS stain reveals purple granules that represent intracellular glycogen and glycoproteins in the cornoid lamella.24 Vacuolated cells in the spinous layer are found beneath the cornoid lamella. Dilated capillaries associated with lymphocytic infiltrate are also often seen beneath the cornoid lamella in the papillary dermis. Most prominently associated with inflammatory changes, DSAP exhibits superficial band-like infiltrate resembling lichenoid qualities.24
Even though a cornoid lamella is characteristic of porokeratosis, it has been identified in other skin lesions as well, including basal cell carcinoma, Bowen’s disease, and solar keratosis; yet, in these lesions, their primary histological characteristics are distinct.26 According to Gray et al, several studies have delineated porokeratosis as a premalignant condition.26
By staining patterns using keratinocyte maturation and differentiation markers such as cytokeratins stained by AE1, AE2, involuvrin, filaggrin, and the growth activation marker psi-3, observations were made concerning the association of porokeratosis and premalignant keratinocyte lesions. Keratinocytes from the center of porokeratosis lesions stain similarly to other premalignant lesions such as actinic keratoses, recessive dystrophic epidermolysis bullosa, and non-healing wounds with a “chronic growth activation” pattern, and this chronic development may be the actual determinant in their predisposition for malignancy.27 Keratinocytes beneath the cornoid lamella stain similarly to those seen in squamous cell carcinomas.28
Differential Diagnosis
Porokeratosis has distinct clinical features, but it may be difficult to differentiate from other diagnosis based on the lesion variant and location. The disseminated superficial variants (DSP and DSAP) might be confused with seborrheic, actinic keratoses along with verucca vulgaris, guttate psoriasis, lichen planus, lichen sclerosus et atrophicus, acrokeratosis verruciformis, and pityriasis rubra pilaris.1,2,29 Clinically, cutaneous T-cell lymphoma or cutaneous sarcoidosis may mimic lesions of DSAP or classic porokeratosis of Mibelli, but histologically, these lesions lack the classic cornoid lamella and commonly contain atypical lymphocytic infiltrates or dermal granulomas, respectively.1
Based on the medical history of our patient, who had systemic sarcoidosis and monoclonal gammopathy, we performed a biopsy of a lesion on her right thigh to rule out associated skin manifestations. The dermatopathology was consistent with features of porokeratosis, including coronoid lamella, attenuated underlying granular layer, and hyperplastic epidermis with few dyskeratotic keratinocytes.
Etiology
Even though porokeratosis was described in the late 1800s, its etiology remains unknown; it is hypothesized to be multifactorial. A widely accepted theory by Reed and Leone explains porokeratosis as being the result of abnormal clones of epidermal cells, which expand peripherally to form a cornoid lamella at the border between the abnormal clonal population and the normal keratinocytes.30,31 Genetic abnormalities may predispose a person to the development of these clones, which could be activated ideopathically or as a result of various stimuli such as sun exposure, viral infection, or immunosuppression through HIV infection, organ transplantation, or photochemotherapy.13,31
Recent genetic analyses and linkage studies have mapped certain variants of porokeratosis to different loci, confirming porokeratosis to be a genetic skin disease, mostly through autosomal dominant inheritance.32 A single locus for PPPD was identified at chromosome 12q24.1-24.2.21
In a study of two Chinese families, two loci for DSAP were mapped to 12q23.2-24.1 and 15q25.1-26.1.18,19 At chromosome 18p11.3 in a large Chinese family, DSP was mapped. This implies that DSAP and DSP originate from two different genetic bases.3
Several arguments in the literature indicate that sun exposure is a risk factor for both DSAP and skin cancers and that age-related malignant transformations may be a link between the two.14 Furthermore, there is a direct correlation between porokeratosis and various epithelial tumors,15 and certain studies have concluded porokeratosis to be a premalignant condition for skin tumors.33
The percentage of patients with porokeratosis-associated skin cancers is estimated to be between 6.9% and 11.6% of all porokeratosis patients,14 with commonly reported skin malignancies being Bowen’s disease, squamous cell carcinoma, and basal cell carcinoma.16
In relation to the different clinical variants of porokeratosis, linear porokeratosis seems to be the most premalignant subtype, with a 19% risk of malignant transformation, followed by porokeratosis palmaris et plantaris disseminata at 9.5%, classic porokeratosis of Mibelli at 7.6%, and DSAP at 3.4%.33
Evidence on a molecular basis also associates porokeratosis with malignant lesions. For example, over-expression of the tumor suppression protein p53 has been detected in the cornoid lamella of porokeratosis patients and in squamous cell carcinomas associated with porokeratosis, leading to the concept that p53 is associated with skin carcinogenesis.28,34 In a study that examined 11 cases of porokeratosis, all lesions showed over-expression of p53 with immunohistochemistry staining.28 Abnormal DNA ploidy has also been recognized in the epidermis of patients with porokeratosis.35 A study comparing cultured fibroblasts derived from porokeratosis cells versus normal cells showed a greater number of chromosomal abnormalities in the diseased cells as well.36
Management
Porokeratosis is rarely symptomatic, yet treatment is indicated not only for cosmesis, but also for the prevention of a possible malignant transformation. It is important to follow and closely monitor patients with porokeratosis to prevent development of cutaneous malignancies.
There is no standardized treatment for porokeratosis because of the diverse clinical presentations as well as the varied responses to treatment. Every treatment reported also carries the risk of a possible recurrence as well as side effects.37
Porokeratosis can be treated with the following approaches: surgical excision,32 curettage,32 electocautery,32 keratolytics,16 cryotherapy,32 topical 5-fluorouracil,1,38 tretinoin,38 CO2 laser,39 585-nm pulsed dye laser,40 Nd:YAG laser,41 and dermabrasion.16 Systemically administered tretinoin may also be a viable option for prophylaxis against carcinogenesis,16 although skeletal and hepatic toxicity should be carefully considered.13 A recent case report of photodynamic therapy for DSAP proved ineffective in three patients.42 More recently, however, patients with porokeratosis were successfully treated with topical 5% imiquimod cream, without scarring or recurrences after 1- to 2-year follow-up.37,43
After discussing the minimal risks of malignant transformation and treatment, our patient was treated with topical 5-fluorouracil cream twice daily with moderate improvement after 2 months of follow-up.
Patient Presentation
A 57-year-old African-American woman presented with violaceous-brown annular plaques and papules with knife-like, double-edge, hyperkeratotic rims on her bilateral thighs and right pretibial areas. (See image above.) These lesions were asymptomatic and gradually appeared over 4 months. The patient’s past medical history was pertinent for systemic sarcoidosis and IgG Kappa monoclonal gammopathy. She denied medication changes within the past 6 months. Her social and family histories were unremarkable. A skin biopsy was performed to determine the diagnosis.
What’s Your Diagnosis?
Diagnosis: Disseminated Superficial Actinic Porokeratosis (DSAP)
Porokeratosis, an epidermal keratinization disorder, is characterized by its unique appearance of hyperkeratotic papules and plaques with double-edged borders. It has six clinical variants, which include porokeratosis of Mibelli, disseminated superficial actinic porokeratosis (DSAP), linear porokeratosis (LP), porokeratosis palmaris et plantaris disseminata (PPPD), porokeratosis punctata palmaris et plantaris (PPPP), and disseminated superficial porokeratosis (DSP). (See Table 1.)
Classical porokeratosis of Mibelli is described as large annular plaques with normal or atrophic centers enclosed by a hyperkeratotic border.1,2,3 Mibelli first described this classic form in 1893 and coined the term “porokeratosis,”4 while Respighi described the disseminated superficial form (DSP).5 Guss et al acknowledged PPPD in 1971,6 while PPPP was designated as a minor type of porokeratosis in 1977.7
DSAP — Most Common Form
Our patient’s skin eruption is the most common form of porokeratosis, DSAP,2 which was first described by Chernosky in 1966.8 Clinical presentation of DSAP usually occurs in the third to fourth decade of life with a greater incidence in women.1 DSAP is most commonly seen in Caucasians with a history of significant sun exposure.9 Although our patient was an African-American female, she did report history of significant sun exposure.
Other Variants
There are other extremely rare variants of porokeratosis that do not fall into the six main subtypes including giant, hyperkeratotic, reticulated, genital and zosteriform.10 Coexistence of different variants of porokeratosis is also fairly uncommon, although cases of linear porokeratosis have been described with DSAP.11,12 Congenital cases are even rarer, yet a 5-year-old girl born with linear porokeratosis who developed DSP at the age of 3 has been noted.13 Recent reports in literature of coexisting porokeratosis with multiple squamous cell carcinomas have also been described.10
Clinical Features
Porokeratosis is usually an asymptomatic skin disorder of benign epidermal proliferation,14 which can be divided into localized and disseminated variants with different clinical presentations. Localized types consist of the classic porokeratosis of Mibelli, LP, and PPPP; disseminated variants consist of DSP, DSAP and PPPD.8,15,16
In terms of the disseminated variants, DSAP presents in middle-aged to elderly patients with many small (0.1 to 0.3 cm in diameter), annular, anhidrotic, and keratotic papules and plaques with slightly elevated hyperkeratotic rims and minimally atrophic centers.1,17,18 Skin lesions of DSAP characteristically affect sun-exposed areas — particularly lower extremities — and an earlier onset of DSAP may be associated with increased exposure to sunlight.19 Conversely, DSP is characterized by small, brown annular lesions with an elevated hyperkeratotic ridge mainly on the extremities in a bilateral, symmetric fashion; its usual age of onset is before age 20.1,3 PPPD is illustrated by keratotic red to brown papules that are initially localized superficially to the palms and soles both bilaterally and symmetrically, but which over a period of several months to years, disseminate throughout the body.1,20,21
The most prominent localized variant of porokeratosis is the classic porokeratosis of Mibelli, which typically first appears during childhood and is described as small asymptomatic keratotic papules or larger plaques with the classic hyperkeratotic ridge that are most commonly unilateral and localized on the extremities.9
Linear porokeratosis, characterized by small keratotic papules with hyperkeratotic borders in linear configuration,3 has an earlier age of onset, affecting children under the age of 10 with congenital cases also reported.22 Linear porokeratosis is more commonly seen as unilateral lesions on distal extremities; however, on very rare occasions, it can present bilaterally on all extremities as well as the trunk.1,16
Exhibiting punctate, keratotic, often spine-like lesions, PPPP lesions are confined to a patient’s palms and soles.9,23
Histology
Porokeratosis is histologically characterized by the presence of a cornoid lamella, a thin column of parakeratotic cells extending through the stratum corneum with loss of granular layers.24 In order to visualize the typical cornoid lamella, the biopsy must be obtained of the raised, peripheral, hyperkeratotic rim.25 Within the parakeratotic column of the cornoid lamella, the horny cells appear homogenous with pyknotic nuclei; the epidermis below this column contains irregularly arranged keratinocytes, with pyknotic nuclei and perinuclear edema. Due to premature keratinization, some cells in the upper stratum malpighii have an eosinophilic cytoplasm, as well. Electron microscopy also shows keratinocyte degeneration in the epidermis below the parakeratotic column.25
The cornoid lamella represents a localized area of faulty keratinization that is regarded as a clonal disease.24 This ridge will show a keratin-filled invagination of the dermis.25 A PAS stain reveals purple granules that represent intracellular glycogen and glycoproteins in the cornoid lamella.24 Vacuolated cells in the spinous layer are found beneath the cornoid lamella. Dilated capillaries associated with lymphocytic infiltrate are also often seen beneath the cornoid lamella in the papillary dermis. Most prominently associated with inflammatory changes, DSAP exhibits superficial band-like infiltrate resembling lichenoid qualities.24
Even though a cornoid lamella is characteristic of porokeratosis, it has been identified in other skin lesions as well, including basal cell carcinoma, Bowen’s disease, and solar keratosis; yet, in these lesions, their primary histological characteristics are distinct.26 According to Gray et al, several studies have delineated porokeratosis as a premalignant condition.26
By staining patterns using keratinocyte maturation and differentiation markers such as cytokeratins stained by AE1, AE2, involuvrin, filaggrin, and the growth activation marker psi-3, observations were made concerning the association of porokeratosis and premalignant keratinocyte lesions. Keratinocytes from the center of porokeratosis lesions stain similarly to other premalignant lesions such as actinic keratoses, recessive dystrophic epidermolysis bullosa, and non-healing wounds with a “chronic growth activation” pattern, and this chronic development may be the actual determinant in their predisposition for malignancy.27 Keratinocytes beneath the cornoid lamella stain similarly to those seen in squamous cell carcinomas.28
Differential Diagnosis
Porokeratosis has distinct clinical features, but it may be difficult to differentiate from other diagnosis based on the lesion variant and location. The disseminated superficial variants (DSP and DSAP) might be confused with seborrheic, actinic keratoses along with verucca vulgaris, guttate psoriasis, lichen planus, lichen sclerosus et atrophicus, acrokeratosis verruciformis, and pityriasis rubra pilaris.1,2,29 Clinically, cutaneous T-cell lymphoma or cutaneous sarcoidosis may mimic lesions of DSAP or classic porokeratosis of Mibelli, but histologically, these lesions lack the classic cornoid lamella and commonly contain atypical lymphocytic infiltrates or dermal granulomas, respectively.1
Based on the medical history of our patient, who had systemic sarcoidosis and monoclonal gammopathy, we performed a biopsy of a lesion on her right thigh to rule out associated skin manifestations. The dermatopathology was consistent with features of porokeratosis, including coronoid lamella, attenuated underlying granular layer, and hyperplastic epidermis with few dyskeratotic keratinocytes.
Etiology
Even though porokeratosis was described in the late 1800s, its etiology remains unknown; it is hypothesized to be multifactorial. A widely accepted theory by Reed and Leone explains porokeratosis as being the result of abnormal clones of epidermal cells, which expand peripherally to form a cornoid lamella at the border between the abnormal clonal population and the normal keratinocytes.30,31 Genetic abnormalities may predispose a person to the development of these clones, which could be activated ideopathically or as a result of various stimuli such as sun exposure, viral infection, or immunosuppression through HIV infection, organ transplantation, or photochemotherapy.13,31
Recent genetic analyses and linkage studies have mapped certain variants of porokeratosis to different loci, confirming porokeratosis to be a genetic skin disease, mostly through autosomal dominant inheritance.32 A single locus for PPPD was identified at chromosome 12q24.1-24.2.21
In a study of two Chinese families, two loci for DSAP were mapped to 12q23.2-24.1 and 15q25.1-26.1.18,19 At chromosome 18p11.3 in a large Chinese family, DSP was mapped. This implies that DSAP and DSP originate from two different genetic bases.3
Several arguments in the literature indicate that sun exposure is a risk factor for both DSAP and skin cancers and that age-related malignant transformations may be a link between the two.14 Furthermore, there is a direct correlation between porokeratosis and various epithelial tumors,15 and certain studies have concluded porokeratosis to be a premalignant condition for skin tumors.33
The percentage of patients with porokeratosis-associated skin cancers is estimated to be between 6.9% and 11.6% of all porokeratosis patients,14 with commonly reported skin malignancies being Bowen’s disease, squamous cell carcinoma, and basal cell carcinoma.16
In relation to the different clinical variants of porokeratosis, linear porokeratosis seems to be the most premalignant subtype, with a 19% risk of malignant transformation, followed by porokeratosis palmaris et plantaris disseminata at 9.5%, classic porokeratosis of Mibelli at 7.6%, and DSAP at 3.4%.33
Evidence on a molecular basis also associates porokeratosis with malignant lesions. For example, over-expression of the tumor suppression protein p53 has been detected in the cornoid lamella of porokeratosis patients and in squamous cell carcinomas associated with porokeratosis, leading to the concept that p53 is associated with skin carcinogenesis.28,34 In a study that examined 11 cases of porokeratosis, all lesions showed over-expression of p53 with immunohistochemistry staining.28 Abnormal DNA ploidy has also been recognized in the epidermis of patients with porokeratosis.35 A study comparing cultured fibroblasts derived from porokeratosis cells versus normal cells showed a greater number of chromosomal abnormalities in the diseased cells as well.36
Management
Porokeratosis is rarely symptomatic, yet treatment is indicated not only for cosmesis, but also for the prevention of a possible malignant transformation. It is important to follow and closely monitor patients with porokeratosis to prevent development of cutaneous malignancies.
There is no standardized treatment for porokeratosis because of the diverse clinical presentations as well as the varied responses to treatment. Every treatment reported also carries the risk of a possible recurrence as well as side effects.37
Porokeratosis can be treated with the following approaches: surgical excision,32 curettage,32 electocautery,32 keratolytics,16 cryotherapy,32 topical 5-fluorouracil,1,38 tretinoin,38 CO2 laser,39 585-nm pulsed dye laser,40 Nd:YAG laser,41 and dermabrasion.16 Systemically administered tretinoin may also be a viable option for prophylaxis against carcinogenesis,16 although skeletal and hepatic toxicity should be carefully considered.13 A recent case report of photodynamic therapy for DSAP proved ineffective in three patients.42 More recently, however, patients with porokeratosis were successfully treated with topical 5% imiquimod cream, without scarring or recurrences after 1- to 2-year follow-up.37,43
After discussing the minimal risks of malignant transformation and treatment, our patient was treated with topical 5-fluorouracil cream twice daily with moderate improvement after 2 months of follow-up.
Patient Presentation
A 57-year-old African-American woman presented with violaceous-brown annular plaques and papules with knife-like, double-edge, hyperkeratotic rims on her bilateral thighs and right pretibial areas. (See image above.) These lesions were asymptomatic and gradually appeared over 4 months. The patient’s past medical history was pertinent for systemic sarcoidosis and IgG Kappa monoclonal gammopathy. She denied medication changes within the past 6 months. Her social and family histories were unremarkable. A skin biopsy was performed to determine the diagnosis.
What’s Your Diagnosis?
Diagnosis: Disseminated Superficial Actinic Porokeratosis (DSAP)
Porokeratosis, an epidermal keratinization disorder, is characterized by its unique appearance of hyperkeratotic papules and plaques with double-edged borders. It has six clinical variants, which include porokeratosis of Mibelli, disseminated superficial actinic porokeratosis (DSAP), linear porokeratosis (LP), porokeratosis palmaris et plantaris disseminata (PPPD), porokeratosis punctata palmaris et plantaris (PPPP), and disseminated superficial porokeratosis (DSP). (See Table 1.)
Classical porokeratosis of Mibelli is described as large annular plaques with normal or atrophic centers enclosed by a hyperkeratotic border.1,2,3 Mibelli first described this classic form in 1893 and coined the term “porokeratosis,”4 while Respighi described the disseminated superficial form (DSP).5 Guss et al acknowledged PPPD in 1971,6 while PPPP was designated as a minor type of porokeratosis in 1977.7
DSAP — Most Common Form
Our patient’s skin eruption is the most common form of porokeratosis, DSAP,2 which was first described by Chernosky in 1966.8 Clinical presentation of DSAP usually occurs in the third to fourth decade of life with a greater incidence in women.1 DSAP is most commonly seen in Caucasians with a history of significant sun exposure.9 Although our patient was an African-American female, she did report history of significant sun exposure.
Other Variants
There are other extremely rare variants of porokeratosis that do not fall into the six main subtypes including giant, hyperkeratotic, reticulated, genital and zosteriform.10 Coexistence of different variants of porokeratosis is also fairly uncommon, although cases of linear porokeratosis have been described with DSAP.11,12 Congenital cases are even rarer, yet a 5-year-old girl born with linear porokeratosis who developed DSP at the age of 3 has been noted.13 Recent reports in literature of coexisting porokeratosis with multiple squamous cell carcinomas have also been described.10
Clinical Features
Porokeratosis is usually an asymptomatic skin disorder of benign epidermal proliferation,14 which can be divided into localized and disseminated variants with different clinical presentations. Localized types consist of the classic porokeratosis of Mibelli, LP, and PPPP; disseminated variants consist of DSP, DSAP and PPPD.8,15,16
In terms of the disseminated variants, DSAP presents in middle-aged to elderly patients with many small (0.1 to 0.3 cm in diameter), annular, anhidrotic, and keratotic papules and plaques with slightly elevated hyperkeratotic rims and minimally atrophic centers.1,17,18 Skin lesions of DSAP characteristically affect sun-exposed areas — particularly lower extremities — and an earlier onset of DSAP may be associated with increased exposure to sunlight.19 Conversely, DSP is characterized by small, brown annular lesions with an elevated hyperkeratotic ridge mainly on the extremities in a bilateral, symmetric fashion; its usual age of onset is before age 20.1,3 PPPD is illustrated by keratotic red to brown papules that are initially localized superficially to the palms and soles both bilaterally and symmetrically, but which over a period of several months to years, disseminate throughout the body.1,20,21
The most prominent localized variant of porokeratosis is the classic porokeratosis of Mibelli, which typically first appears during childhood and is described as small asymptomatic keratotic papules or larger plaques with the classic hyperkeratotic ridge that are most commonly unilateral and localized on the extremities.9
Linear porokeratosis, characterized by small keratotic papules with hyperkeratotic borders in linear configuration,3 has an earlier age of onset, affecting children under the age of 10 with congenital cases also reported.22 Linear porokeratosis is more commonly seen as unilateral lesions on distal extremities; however, on very rare occasions, it can present bilaterally on all extremities as well as the trunk.1,16
Exhibiting punctate, keratotic, often spine-like lesions, PPPP lesions are confined to a patient’s palms and soles.9,23
Histology
Porokeratosis is histologically characterized by the presence of a cornoid lamella, a thin column of parakeratotic cells extending through the stratum corneum with loss of granular layers.24 In order to visualize the typical cornoid lamella, the biopsy must be obtained of the raised, peripheral, hyperkeratotic rim.25 Within the parakeratotic column of the cornoid lamella, the horny cells appear homogenous with pyknotic nuclei; the epidermis below this column contains irregularly arranged keratinocytes, with pyknotic nuclei and perinuclear edema. Due to premature keratinization, some cells in the upper stratum malpighii have an eosinophilic cytoplasm, as well. Electron microscopy also shows keratinocyte degeneration in the epidermis below the parakeratotic column.25
The cornoid lamella represents a localized area of faulty keratinization that is regarded as a clonal disease.24 This ridge will show a keratin-filled invagination of the dermis.25 A PAS stain reveals purple granules that represent intracellular glycogen and glycoproteins in the cornoid lamella.24 Vacuolated cells in the spinous layer are found beneath the cornoid lamella. Dilated capillaries associated with lymphocytic infiltrate are also often seen beneath the cornoid lamella in the papillary dermis. Most prominently associated with inflammatory changes, DSAP exhibits superficial band-like infiltrate resembling lichenoid qualities.24
Even though a cornoid lamella is characteristic of porokeratosis, it has been identified in other skin lesions as well, including basal cell carcinoma, Bowen’s disease, and solar keratosis; yet, in these lesions, their primary histological characteristics are distinct.26 According to Gray et al, several studies have delineated porokeratosis as a premalignant condition.26
By staining patterns using keratinocyte maturation and differentiation markers such as cytokeratins stained by AE1, AE2, involuvrin, filaggrin, and the growth activation marker psi-3, observations were made concerning the association of porokeratosis and premalignant keratinocyte lesions. Keratinocytes from the center of porokeratosis lesions stain similarly to other premalignant lesions such as actinic keratoses, recessive dystrophic epidermolysis bullosa, and non-healing wounds with a “chronic growth activation” pattern, and this chronic development may be the actual determinant in their predisposition for malignancy.27 Keratinocytes beneath the cornoid lamella stain similarly to those seen in squamous cell carcinomas.28
Differential Diagnosis
Porokeratosis has distinct clinical features, but it may be difficult to differentiate from other diagnosis based on the lesion variant and location. The disseminated superficial variants (DSP and DSAP) might be confused with seborrheic, actinic keratoses along with verucca vulgaris, guttate psoriasis, lichen planus, lichen sclerosus et atrophicus, acrokeratosis verruciformis, and pityriasis rubra pilaris.1,2,29 Clinically, cutaneous T-cell lymphoma or cutaneous sarcoidosis may mimic lesions of DSAP or classic porokeratosis of Mibelli, but histologically, these lesions lack the classic cornoid lamella and commonly contain atypical lymphocytic infiltrates or dermal granulomas, respectively.1
Based on the medical history of our patient, who had systemic sarcoidosis and monoclonal gammopathy, we performed a biopsy of a lesion on her right thigh to rule out associated skin manifestations. The dermatopathology was consistent with features of porokeratosis, including coronoid lamella, attenuated underlying granular layer, and hyperplastic epidermis with few dyskeratotic keratinocytes.
Etiology
Even though porokeratosis was described in the late 1800s, its etiology remains unknown; it is hypothesized to be multifactorial. A widely accepted theory by Reed and Leone explains porokeratosis as being the result of abnormal clones of epidermal cells, which expand peripherally to form a cornoid lamella at the border between the abnormal clonal population and the normal keratinocytes.30,31 Genetic abnormalities may predispose a person to the development of these clones, which could be activated ideopathically or as a result of various stimuli such as sun exposure, viral infection, or immunosuppression through HIV infection, organ transplantation, or photochemotherapy.13,31
Recent genetic analyses and linkage studies have mapped certain variants of porokeratosis to different loci, confirming porokeratosis to be a genetic skin disease, mostly through autosomal dominant inheritance.32 A single locus for PPPD was identified at chromosome 12q24.1-24.2.21
In a study of two Chinese families, two loci for DSAP were mapped to 12q23.2-24.1 and 15q25.1-26.1.18,19 At chromosome 18p11.3 in a large Chinese family, DSP was mapped. This implies that DSAP and DSP originate from two different genetic bases.3
Several arguments in the literature indicate that sun exposure is a risk factor for both DSAP and skin cancers and that age-related malignant transformations may be a link between the two.14 Furthermore, there is a direct correlation between porokeratosis and various epithelial tumors,15 and certain studies have concluded porokeratosis to be a premalignant condition for skin tumors.33
The percentage of patients with porokeratosis-associated skin cancers is estimated to be between 6.9% and 11.6% of all porokeratosis patients,14 with commonly reported skin malignancies being Bowen’s disease, squamous cell carcinoma, and basal cell carcinoma.16
In relation to the different clinical variants of porokeratosis, linear porokeratosis seems to be the most premalignant subtype, with a 19% risk of malignant transformation, followed by porokeratosis palmaris et plantaris disseminata at 9.5%, classic porokeratosis of Mibelli at 7.6%, and DSAP at 3.4%.33
Evidence on a molecular basis also associates porokeratosis with malignant lesions. For example, over-expression of the tumor suppression protein p53 has been detected in the cornoid lamella of porokeratosis patients and in squamous cell carcinomas associated with porokeratosis, leading to the concept that p53 is associated with skin carcinogenesis.28,34 In a study that examined 11 cases of porokeratosis, all lesions showed over-expression of p53 with immunohistochemistry staining.28 Abnormal DNA ploidy has also been recognized in the epidermis of patients with porokeratosis.35 A study comparing cultured fibroblasts derived from porokeratosis cells versus normal cells showed a greater number of chromosomal abnormalities in the diseased cells as well.36
Management
Porokeratosis is rarely symptomatic, yet treatment is indicated not only for cosmesis, but also for the prevention of a possible malignant transformation. It is important to follow and closely monitor patients with porokeratosis to prevent development of cutaneous malignancies.
There is no standardized treatment for porokeratosis because of the diverse clinical presentations as well as the varied responses to treatment. Every treatment reported also carries the risk of a possible recurrence as well as side effects.37
Porokeratosis can be treated with the following approaches: surgical excision,32 curettage,32 electocautery,32 keratolytics,16 cryotherapy,32 topical 5-fluorouracil,1,38 tretinoin,38 CO2 laser,39 585-nm pulsed dye laser,40 Nd:YAG laser,41 and dermabrasion.16 Systemically administered tretinoin may also be a viable option for prophylaxis against carcinogenesis,16 although skeletal and hepatic toxicity should be carefully considered.13 A recent case report of photodynamic therapy for DSAP proved ineffective in three patients.42 More recently, however, patients with porokeratosis were successfully treated with topical 5% imiquimod cream, without scarring or recurrences after 1- to 2-year follow-up.37,43
After discussing the minimal risks of malignant transformation and treatment, our patient was treated with topical 5-fluorouracil cream twice daily with moderate improvement after 2 months of follow-up.
