Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants

Abstract

Porokeratosis is a heterogeneous group of keratinising disorders characterised by the presence of particular microscopic structural changes, namely the presence of the cornoid lamella. This structure develops as a consequence of a defective isoprenoid pathway, critical for cholesterol synthesis. Commonly recognised variants include disseminated superficial actinic porokeratosis, disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar porokeratosis (including porokeratosis palmaris et plantaris disseminata and punctate porokeratosis), linear porokeratosis, verrucous porokeratosis (also known as genitogluteal porokeratosis), follicular porokeratosis and porokeratoma. Apart from the clinical presentation and epidemiology of each variant listed, this review aims at providing up-to-date information on the precise genetic background, introduces imaging methods facilitating the diagnosis (conventional and ultraviolet-induced fluorescence dermatoscopy, reflectance confocal microscopy and pathology), discusses their oncogenic potential and reviews the literature data on the efficacy of the treatment used, including the drugs directly targeting the isoprenoid-mevalonate pathway.

Keywords: dermatoscopy; genetics; malignancy; mevalonate–isoprenoid pathway; porokeratosis; reflectance confocal microscopy; treatment; ultraviolet radiation.

Figure 1

Small atrophic, annular, hyperkeratotic lesions (black arrows) distributed over sun-exposed areas (incl. upper and lower legs, dorsa of the hands, forehead) in elderly women with disseminated superficial actinic porokeratosis (A–D).

Figure 2

Dermatoscopy of disseminated superficial actinic porokeratosis (magnification 20×): central atrophic pink–tan area with polarising-specific white lines (black arrow), small white areas (black arrowheads) and vascular polymorphism (dots, linear serpentine and linear glomerular vessels; red arrows, red arrowheads and red V-shaped arrows, respectively), surrounded by a continuous yellowish double-edged keratin rim (yellow arrow). Radially arranged peripheral scaling (yellow arrowhead) can be observed on both sides of cornoid lamella (A). “Ink test”: Colouring the lesion and wiping out excessive pigment enhances the visibility of the keratotic rim, especially in non-obvious cases (B). In this case, brown pen ink was used, yet whiteboard marker or gentian violet can also be used.

Figure 3

Reflectance confocal microscopy of disseminated superficial actinic porokeratosis: epidermal layer with parakeratosis (red asterisk) (A), elongated vessels in the lower parts of the epidermal layer (red arrow) and spongiosis (yellow arrow) (B), hyperkeratosis in the epidermal furrow (yellow arrow) (C).

Figure 4

Pathology of disseminated superficial actinic porokeratosis shows cornoid lamella (black arrowhead) along with typical diffuse epidermal atrophy, agranulosis, basal keratinocyte vacuolisation (yellow arrowhead) and superficial inflammatory infiltrate in the upper dermis (white arrowhead) (original objective magnification 20×).

Figure 5

The mevalonate–isoprenoid pathway involved in pathogenesis of porokeratoses. Legend: ACAT—Acetoacetyl-CoA thiolase, FDPS—Farnesyl diphosphate synthase, FDFT—Farnesyl diphosphate farnesyltransferase, GGPS—Geranylgeranyl pyrophosphate synthase, HMGCoA—3-hydroxy-3-methylglutaryl-CoA, HMGCR—3-hydroxy-3-methylglutaryl-CoA reductase, HMGCS—3-hydroxy-3-methylglutaryl-CoA synthase, IDI—Isopentenyl pyrophosphate isomerase, MVD—Mevalonate-5-pyrophosphate decarboxylase, MVK—Mevalonate-5-kinase, PMVK—Phosphomevalonate kinase.

Figure 6

Comparison of conventional non-contact non-polarised dermatoscopy (A) and non-contact polarised dermatoscopy (B), with novel imaging techniques, namely ultraviolet-induced fluorescence dermatoscopy (UVFD; 365 nm) (C) and sub-UV reflectance dermatoscopy (sUVRD; 405 nm) (D). Note the differences in visualisation of annular keratin rim (yellow arrow), inner pink structureless area (black arrow), follicular plugging (white arrow) and vascular pattern of dots (red arrow).

Figure 7

Solitary, asymptomatic annular porokeratosis of Mibelli located on an extensor aspect of a lower leg in a middle-aged woman (black arrowhead).

Figure 8

Dermatoscopy of porokeratosis of Mibelli reveals a central hypopigmented area with polarising-specific white lines (black arrow), small white areas (black arrowheads) and dotted and coiled vessels (red arrows and red V-shaped arrows, respectively) surrounded by an interrupted yellowish keratin rim with a double-edged outline (“white track”) (yellow arrows). Within this rim, follicular plugs can be seen (white arrows). Of note, dotted vessels and radially arranged peripheral scaling (yellow arrowhead) can be seen at the lesion’s outer margin (magnification 20×).

Figure 9

Single- (A) or double-edged (B) cornoid lamella (black arrowheads) in PM, with typical epidermal invagination (red arrowheads) and papillomatosis (yellow arrowheads) noted in surrounding skin. Hyperkeratosis (black arrows), irregular acanthosis (red arrows), basal vacuolisation (yellow arrows), single coloids (basal apoptotic keratinocytes; blue arrows), as well as mid-dermal lymphocytic inflammatory infiltrate (white arrowhead) can be observed (original objective magnification 20×).

Figure 10

Clinical presentation of linear porokeratosis. Linear distribution of brown keratotic papules (black arrowhead) along the posterior part of the left leg in middle-aged women.

Figure 11

Dermoscopy of linear porokeratosis reveals white continuous rim of scales (cornoid lamella) (yellow arrows) surrounding central depigmented or pinkish–brownish areas (black arrows) with follicular plugs (white arrows). Pigmented dots can be appreciated at the outer margin of cornoid lamellae (black arrowheads).

Figure 12

Histopathology of linear porokeratosis. A classical basket weave hyperkeratosis (red arrow) is interrupted by a single parakeratotic column delved into epidermis (cornoid lamella; black arrowhead). A sparse inflammatory infiltrate underneath the structure (white arrowhead) can be noted (original objective magnification 20×).

Figure 13

Clinical presentation of porokeratosis plantaris, palmaris et disseminata (PPPD) in elderly men who developed cutaneous squamous cell carcinoma within the lesion. The punctate keratotic lesions affected palms and soles (black arrowheads) (A), whereas the annular lesions were distributed in a reticulate fashion on the forearms (white arrowheads) (B) and lower legs.

Figure 14

Pathology of the forearm (A) and plantar (B) lesions in a middle-aged man with porokeratosis plantaris, palmaris et disseminata (PPPD) showing cornoid lamella (black arrowheads), papillomatosis with hypogranulosis (yellow arrowheads and green arrowheads, respectively), dyskeratotic keratinocytes (blue arrows) and mild superficial dermal inflammatory infiltrate (white arrowheads) (original objective magnification 20×).

Figure 15

Verrucous porokeratosis. Clinical image of genitogluteal verrucous porokereratosis featuring prominent keratotic rim (black arrowheads) in a middle-aged man with a “butterfly-shaped” distribution over the gluteal region (A). Isolated penoscrotal verrucous porokeratosis affecting the penis shaft and preputium (white arrowheads). The patient had a 15-year history of treatment for lichen planus (B).

Figure 16

Dermatoscopy of penoscrotal verrucous porokeratosis exhibiting white keratotic rim (cornoid lamella; yellow arrows).

Figure 17

Pathology of verrucous porokeratosis. Multiple cornoid lamellae (black arrowheads) in a hypertrophic, irregularly papillomatous epidermis (yellow arrowheads), dilated papillary vessels (red arrowheads) and upper dermal lymphocytic infiltrate (white arrowheads) (original objective magnification 10×) (A). Multiple cornoid lamellae in hypertrophic, digitate epidermis with vacuolised basal keratinocytes (yellow arrows) and thinning/focal absence of stratum granulosum (green arrowheads) (original objective magnification 20×) (B). Parakeratotic column (retention of keratinocyte nuclei), delved into the epidermis. Hypogranulosis with multiple dyskeratotic cells (blue arrow) extending from basal to spinous layer and single necrotic keratinocytes can be appreciated (blue arrowheads) (original objective magnification 20×) (C).

Figure 18

Cutaneous squamous cell carcinoma developing on the lower leg in elderly female with disseminated superficial actinic porokeratosis (black arrowhead) (A). Dermatoscopy reveals white continuous keratotic rim (cornoid lamella; yellow arrow) that limits homogeneous pinkish–tan area with linear glomerular vessels (black arrow and red arrowhead, respectively). This vascular pattern developing due to venous stasis is typical for lower legs (B). Dermatoscopy displays pink–whitish structureless area (black arrow) with a central keratin plug (white arrow) and vascular polymorphism suggestive of squamous cell carcinoma (magnification 20×) (C).