Porokeratosis: An enigma beginning to unravel

Introduction

Porokeratosis is an enigmatic skin condition in terms of its etiopathogenesis, clinical presentation, histopathology and treatment options. Considered as a clonal keratinizing disorder of uncertain etiology,¹ it clinically manifests as solitary or multiple atrophic patches surrounded by a hyperkeratotic ridge-like border which histopathologically corresponds to the cornoidlamella.² A comprehensive English language literature search was done for porokeratosis across multiple databases (PubMed, EMBASE, MEDLINE and Cochrane) for keywords (alone and in combination). MeSH as well as nonMeSH terms such as “porokeratosis,” “history,” “classification,” “pathogenesis,” “clinical variants,” “histology,” “cornoid lamellae,” “dermoscopy” and “treatment” were taken into consideration, for the purpose of this narrative review.

Porokeratosis was first described by Neumann in 1875.³ However, the naming of the condition is attributed to Mibelli, an Italian dermatologist, who coined the term “porokeratosis” because of the involvement of eccrine ostia in his patient.⁴ A superficial disseminated form of porokeratosis was described by Respighi in 1893⁵ and Andrews in 1937.⁶ The linear variant was described by Truffi in 1905.⁷ The lesions of disseminated superficial actinic porokeratosis were described by Chernosky and Freeman in 1966.⁸ Porokeratosis palmaris et plantaris disseminata was added to the spectrum in 1971.⁹

Porokeratosis is slightly commoner in males.¹⁰ The lesions may be found anywhere on the body (most commonly extremities), though mucosal involvement is very rare.¹¹

Classification

Porokeratosis is mainly classified into localized and generalized forms. Common localized variants are classical porokeratosis of Mibelli, linear porokeratosis, punctate porokeratosis, solar facial porokeratosis and genital porokeratosis.^12,13 Generalized variants are disseminated superficial porokeratosis, disseminated superficial actinic porokeratosis and disseminated palmoplantar porokeratosis. Unusual variants include hyperkeratotic porokeratosis, pruritic popular porokeratosis, verrucous porokeratosis (localized to buttocks)¹⁴ and reticulate porokeratosis. A simplified classification is presented in Table 1.

Pathogenesis

Previously, it was assumed that cornoid lamellae emerge from sweat pores, but it was eventually understood that this concept was not correct. Ultraviolet light exposure, electron beam therapy, extensive radiation therapy, immunosuppression, transplant procedures, immunodeficiency syndromes, chronic renal failure, chronic liver disease, infections, hematological malignancies including lymphomas, HIV infection and hepatitis C virus infection have all been implicated in the pathogenesis.^15-25 Drugs such as etanercept and adalimumab have also been implicated.

Local and systemic immunosuppression leading to reduction of immune surveillance and dysregulated proliferation of abnormal keratinocyte clones has been a well- accepted theory. There was also growing evidence of upregulation of genes involved in wound healing, epidermal differentiation (S100 calcium-binding protein) and regulation of T-cell-mediated immune responses, especially in disseminated superficial actinic porokeratosis.²⁶

Abnormal keratinocyte apoptosis was a proposed pathogenic factor in porokeratosis. This was best exemplified again in disseminated superficial actinic porokeratosis, which showed the presence of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) - positive apoptotic cells seen under the conical lamellar structure. Abnormal apoptosisleading to abnormal loricrin expression affecting terminal keratinocyte differentiation and finally to dyskeratosis was another favored theory of pathogenesis.²⁷

It is now understood that abnormalities in the mevalonate pathway are responsible for the pathogenesis of porokeratosis. Abnormalities in the genes MVD (mevalonate decarboxylase), mevalonate kinase, PMVK (phosphomevalonate kinase), FDPS (farnesyl diphosphate synthase) and solute carrier family 17 member 9 (SLC17A9) have been found to be pathogenic in porokeratosis.²⁸ To date, at least 173 variations in mevalonate kinase, 14 variations in mevalonate decarboxylase, seven variations in phosphor mevalonate kinase and seven variations in farnesyl diphosphate synthase have been associated with porokeratosis. The complex mevalonate pathway is required for generation of isoprenoids, dolichol, ubiquinone, isopentenyl adenine and farnesyl pyrophosphate. These are key intermediate products required for cholesterol and sterol biosynthesis. They also act as ligands for hormone and growth receptors. Since cholesterol forms an important constituent of the cell membrane and affects many processes such as anti -inflammatory and oxidative stress reactions, epidermal differentiation and migration of cells, variations in the mevalonate pathway affect cholesterol and steroid biosynthesis and thereby result in abnormal differentiation of keratinocytes leading to the disease.²⁹

Disseminated superficial actinic porokeratosis is described as an autosomal dominant disease with five loss-of-function mutations identified on linkage analysis: 12q23•2-q24•1,12q24•1-q24•2,15q25•1-q26•1,1p31•3-q31•1and16q24•1-q24•3.³⁰ Mitochondrial dysfunction induced by mevalonate kinase (MVK) mutations may be an important contributory mechanism in disseminated superficial actinic porokeratosis pathogenesis, since mevalonate kinase may have a protective effect on apoptosis of keratinocytesinduced by ultraviolet-A spectrum light. The familial inheritance of disseminated superficial actinic porokeratosis has also been associated with mutations in SSH1, ARPC3 and SART3 genes. Disseminated superficial actinic porokeratosis is also considered a benign intraepidermal neoplastic process and is one of the genetic tumor disorders explained by Knudson’s two-hit hypothesis.

Segmental disseminated superficial actinic porokeratosis³¹ is believed to develop in a background of genetic alterations of keratinocytes in early embryogenesis leading to altered activity of regulatory proteins.³² Linear porokeratosis has been observed in monozygotic twins.³³

Variants such as verrucous porokeratosis, genital porokeratosis and pruritic papular porokeratosis are precipitated by friction, scratching, long-term compression, partial moisture and chronic skindisease. Burns and infections have also been proposed as inciting factors in porokeratosis.^34,35

Bullous changes in porokeratosis are attributed to underlying edema and localized extravasation of interstitial fluid. Morgan et al. postulated that abnormal keratinocytes are unable to provide adequate intercellular junctions, leading to such extravasation.³⁶

Clinical features of individual variants

Porokeratosis of mibelli

This classical variant is characterized by solitary plaques with a thread-like hyperkeratotic margin [Figure 1], most commonly located on the extremities.³⁷ Other sites of involvement include the face, genitalia and trunk. Lesions are usually asymptomatic and persistent, though uncommonly they may resolve spontaneously.

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Figure 1:

Classical solitary plaque of porokeratosis of Mibelli with central atrophy and peripheral keratoticrim

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Disseminated superficial actinic porokeratosis

Currently considered the most common variant of porokeratoses worldwide, this is an autosomal dominant dermatosis, presenting with asymptomatic, bilaterally symmetrical and disseminated brown, annular, keratotic lesions, most commonly distributed over the sun-exposed extensor surface so flower extremities, arms and face in middle-aged women [Figure 2].³⁸ The axillae, groins, perianal region, palms, soles and mucous membranes are spared. Lesions have atrophic centre and are surrounded by thin, elevated and furrowed, palpable keratotic rim. Sun exposure is a prominent etiological factor.

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Figure 2:

Disseminated superficial actinic porokeratosis on the face

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Genital porokeratosis

The first case of porokeratosis localized to the genitalia was described by Helfman and Poulos.⁴² Since then, numerous cases have been reported, and this is now proposed to be a distinct clinical entity.^43,44 Lesions start as erythematous papules which progress to plaques, nodules or ulcers.^45,46 Various presentations of genital porokeratosis have been observed:^47,48

• Classical porokeratosis of Mibelli-like: round atrophic patches with an elevated rim, located over the penis, scrotum and pubic region^49-51

• Hyperkeratotic variant: plaques with a thickened central region and a raised hyperkeratotic margin, located over the perianal region and buttocks

• Porokeratosis ptychotropica: presenting with butterfly-shaped plaques and verrucous hyperplasia, usually seen on the buttocks [Figure 3].^52-58 Satellite lesions in the periphery may sometimes be noted. Anal mucosa is not affected. Lucker et al., in 1995 coined the term “porokeratosis ptychotropica” (Greek word ptyche meaning fold and trope meaning turning, to emphasize the flexural location).⁵⁹ Other terms for this condition include verrucous porokeratosis, hyperkeratotic porokeratosis, follicular porokeratosis and genitogluteal porokeratosis. Stone et al. came across a similar condition, but it was associated with pruritus and they coined the term “perianal inflammatory verrucous porokeratosis.”⁶⁰ This rare condition has mostly been seen in adults.

• Ulceroproliferative variant: round ulcerated plaques, over the penis and scrotum.⁶¹

• Verrucous variant: keratotic and hypertrophic plaques and nodules in the genito-crural region¹⁴

• Penoscrotal variant: typically seen in young men in their third decade of life. Patients present with severely pruritic plaques and patches with a rough granular surface, distributed over the shaft of penis and anterior scrotum.⁶²

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Figure 3:

Classic butterfly lesion of porokeratosis ptychotropica

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The genitalvariant occurs mainly in middle aged males, often with severe pruritus. Diagnosis is usually delayed due to atypical location and morphology.

The current consensus is that all genital porokeratosis can be grouped under a single entity named porokeratosis ptychotropica and all the genital types described as variants thereof. No etiological risk factor for this variant has been identified, unlike the others. Malignant transformation also usually does not occur.

Linear porokeratosis

In this variant, the lesions of porokeratosis are distributed in a linear fashion (may or may not be blaschkoid). During infancy or early childhood, linear arrangement of papules and plaques with the typical elevated peripheral ridge may be observed unilaterally on limbs usually and rarely on trunk, head and/ or neck [Figure 4]. The lesions usually follow a dermatomal distribution.^63-68 Loss of heterozygosity has been proposed as the pathomechanism and this could be responsible for the higher chances of malignant transformation.⁶⁹ No inheritance is, however, reported. The incidence of malignancy reported with this variant is as high as 20%.

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Figure 4:

Linear porokeratosis on the foot and ankle

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Punctate porokeratosis

The variant is typified by the development of numerous asymptomatic, minute, hyperkeratotic papules within, raised margins distributed over the palms and soles [Figures 5 and 6]. Patients may have other variants of porokeratosis (classical type and linear), in association with punctate porokeratosis.

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Figure 5:

Punctate porokeratosis of palms

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Figure 6:

Punctate porokeratosis of soles

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Dermoscopy

Dermoscopy of porokeratotic lesions reveals central brownish discoloration along with blue-gray dots, surrounded by a single hypopigmented band and a peripheral “white track.”⁹⁰ Central scarring and enlarged capillaries are seen. Dermoscopy demonstrates iodine absorption by the cornoid lamella after polyvinyl-pyrrolidone-iodine application on the skin. The furrow ink test makes the ridge and rim more prominent. UV dermoscopy reveals a ‘diamond neck lace’ appearance at the borders.

Histopathology

The histologic hallmark is the presence of cornoid lamella, which is a tightly packed thin column of parakeratotic cells overlying a zone of focal hypogranulosis. It was regarded by Wade and Ackerman as a microscopic reaction pattern in 1980. It is an important diagnostic criterion that consists of a sloping column of parakeratosis associated with loss of the granular layer and underlying vacuolated keratinocytes, within a diffusely thin epidermis [Figure 7]. Lymphocytic inflammation of variable density, usually located in the papillary dermis, represents another reproducible finding. One may observe the presence of dyskeratotic keratinocytes below the spinous layer.⁹¹ The papillary dermis beneath the cornoid lamella contains a moderately dense inflammatory infiltrate and dilated capillaries. The cornoid lamella sometimes focally extends into the hair follicles and intra epidermal eccrine sweat gland ducts.

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Figure 7:

Cornoid lamella on histopathology. H&E stain: × 400

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Cornoid lamellae are usually solitary and located on one side of the clinical lesion in biopsies of classical porokeratosis of Mibelli. However, multiple cornoid lamellae have been observed in porokeratoma, penoscrotal porokeratosis and porokeratosis ptychotropica. They may develop around the adnexae (follicular infundibula and eccrine ostia) in porokeratotic eccrine ostial and dermal duct nevi. The presence of cornoid lamellae in the absence of classical clinical features of porokeratosis has been suggested to be an epidermal reaction pattern, which could be steroid-responsive or a forme fruste of longstanding disease.^92,93 Rarely, dermal amyloid deposits may be noted in cases of verrucous porokeratosis in underlyingtuberculosis cases.⁹⁴

Viral warts, actinic keratoses and some ichthyoses like ichthyosis hystrix may also show cornoid lamellae on histology.⁹⁵ Psoriasis vulgaris, dermatomyositis (Wong type), atypical keratosis lichenoides chronica (atypical Nekam’s disease), pachyonychia congenita, verrucous epidermal nevus, squamous and basal cell carcinoma scan rarely show cornoid lamellae. All of these conditions can be considered as histological mimickers of porokeratosis.

Reflectance photo microscopy can also be used as a mode of diagnosis. It is found to correlate well with horizontal biopsy and dermoscopic findings. Architectural disarray with loss of normal “honeycomb” pattern is seen in the center of the lesion, while in the periphery, less refractile destructured areas containing more refractile amorphous substance correlating with cornoid lamella is present.

Differential Diagnosis

The classical type is usually too typical in its appearance to be mistaken for some other entity. However, minute lesions of porokeratosis may be confused with actinic keratoses, stucco keratoses, verruca plana, lichen sclerosus et atrophicus, lichen planus and acrokeratosis verruciformis.

Differential diagnosis of disseminated superficial actinic porokeratosis includes guttate psoriasis, actinic keratosis, tinea corporis and pityriasis rosea.

The diagnosis of genitocrural porokeratosis is difficult and it closely mimics inverse psoriasis, tuberculosis verrucose cutis, viral warts, verrucous lichen planus, lichen simplex chronicus, lichen sclerosus, dermatophytosis, candidiasis, secondary syphilis, acrodermatitis enteropathica, epidermal nevus, Hailey-Hailey disease, Darier disease and extramammary Paget disease.

Punctate porokeratosis should be differentiated from punctate keratoderma and plantar warts. Porokeratotic eccrine ostial and dermal ductal nevus is usually confused with nevus comedonicus, linear verrucous epidermal nevus, inflammatory linear verrucous epidermal nevus (ILVEN), linear psoriasis, linear porokeratosis, dilated pore nevus, linear lichen planus, punctate palmoplantar keratoderma and punctate porokeratosis. Histopathology helps in differentiating the differentials from each other.

Complications

Long standing cases of porokeratosis may undergo malignant transformation (Bowen disease, squamous cell carcinoma, basal cell carcinoma and melanoma). Other complications include ulceration, soft-tissue destruction, disfigurement,⁹⁶ pseudoainhum with amputation and development of cutaneous horn.^74,97

Treatment

General measures include avoidance of triggering factors and addressing the underlying cause of immunosuppression (if any). Strict photo protection and application of sunscreens and emollients are advisable. Looking out for any signs of malignancy is another corner stones of management.

Conclusion

Porokeratosis is usually a benign dermatosis, except some variants (linear and giant) where aggressive treatment is required to prevent the development of malignancies. Patients with genitocrural porokeratosis, disseminated superficial actinic porokeratosis and disseminated superficial porokeratosis are often difficult to manage and the search for an effective and safe modality goes on. The abnormalities in mevalonate metabolism now being the prime pathogenetic theory, future therapeutic modalities of this enigmatic disease may likely be based on this pathway.