Continuing Education Activity

Porokeratosis is an uncommon dermatologic disorder that presents with keratotic papules or annular plaques featuring an elevated border. The condition typically occurs on sun-exposed skin, most often in the fifth decade of life, but can occur at any age and with similar frequencies in males and females. The increased occurrence of disseminated superficial actinic porokeratosis on sun-exposed skin likely indicates that ultraviolet (UV) light is a risk factor. Although porokeratosis is usually an acquired disease, there is often a familial predisposition that could signify a hereditary component. 

This activity reviews the clinical manifestations of porokeratosis, including variants such as disseminated superficial actinic porokeratosis, classical porokeratosis of Mibelli, linear porokeratosis, and other rare types, each exhibiting unique presentations and challenges in diagnosis and management. The session also delves into histologic features, notably the presence of coronoid lamella, aiding in accurate diagnosis through biopsy of the elevated border. The role of UV light as a risk factor in the development of porokeratosis is discussed, emphasizing the importance of surveillance and management. Attendees will gain insights into the complexities of therapeutic interventions, including topical, systemic, and surgical modalities, without standardized treatment guidelines. With a focus on evaluation, treatment options, and the risk of malignant transformation, this session aims to equip healthcare professionals with a comprehensive understanding of Porokeratosis, facilitating an enhanced team-based approach to patient care and surveillance.

Objectives:

• Apply the comprehensive physical examination techniques necessary to identify and differentiate porokeratosis lesions from other dermatological conditions.

• Implement biopsy procedures targeting the characteristic elevated borders to confirm the diagnosis of porokeratosis.

• Assess various management approaches for porokeratosis, encompassing topical, systemic, and surgical interventions, and identify individualized treatment plans based on lesion characteristics and patient-specific factors. 

• Coordinate care between dermatologists, oncologists, pathologists, and other healthcare providers to apply diverse expertise, facilitating accurate diagnosis, treatment selection, and long-term surveillance of porokeratosis.

Introduction

Porokeratosis is an uncommon disorder of keratinization that presents with keratotic papules or annular plaques with an elevated border.[1] The distinct histologic hallmark of porokeratosis is cornoid lamella, a column of tightly fitted parakeratotic cells in the upper epidermis.[2][3] There are multiple clinical variants of porokeratosis, including:

• Disseminated superficial actinic porokeratosis
• Classical porokeratosis of Mibelli
• Porokeratosis plantaris, palmaris, et disseminate
• Linear porokeratosis [2] 

Additionally, rare variants include:

• Genitogluteal porokeratosis
• Facial porokeratosis
• Giant porokeratosis
• Porokeratosis ptychotropica
• Hypertrophic verrucous porokeratosis
• Eruptive pruritic papular porokeratosis
• Follicular porokeratosis 
• Reticulate porokeratosis [1] 

Variants can occur together but rarely do.[1][4][5] Porokeratosis is a precancerous lesion that can undergo malignant transformation.[6] Evaluation of porokeratosis is best conducted with a biopsy of the elevated border. Although multiple therapies exist for porokeratosis (including topical, systemic, and surgical), there are no standard guidelines for treatment.[7]

Etiology

Despite being first described over a century ago, the etiology and pathology of porokeratosis are unclear, complex, and multifactorial.[3] Suggested etiologies include ultraviolet (UV) light, repeated frictional trauma, genetics, infectious agents, malignancy, and immunosuppression (ie. transplant patients).[8] [9] [10] There are six clinical variants of porokeratosis: disseminated superficial porokeratosis (DSP), disseminated superficial actinic porokeratosis (DSAP), eruptive disseminated porokeratosis (EDP), porokeratosis of Mibelli, linear porokeratosis, and punctate palmoplantar porokeratosis.[10] [11]. Disseminated superficial actinic porokeratosis, the most common variant of porokeratosis, has an autosomal dominant inheritance pattern with incomplete penetrance.[12] [12] Furthermore, a mutation in the mevalonate kinase gene seen in DSAP is responsible for a crucial role in the cholesterol synthesis pathway and UV light protection: a finding that prompted the exploitation of important medications in the treatment of the disease.[10] There is a known link between the development of porokeratosis and UV light exposure, and experimental studies have induced the formation of disseminated superficial actinic porokeratosis.[13] [13] 

Certain drugs and treatment modalities are also associated with the formation of porokeratosis.[14] [11] [15] [16]. A systematic review identified 26 patients with drug-induced porokeratosis and found the most common therapies leading to porokeratosis formation are biologic use, phototherapy, and radiotherapy.[11] [11]

Porokeratosis of Mibelli and disseminated superficial porokeratosis are often associated with systemic immunosuppression therapy, and the prevalence of porokeratosis in organ transplant patients on systemic immunosuppression therapy is 10.68%, according to one study.[3][17] [3] [17]

Among case reports in the literature, there is inconsistency regarding the timing of onset of porokeratosis after immunosuppression therapy. Reports detail that these lesions can appear anywhere from 3 weeks to 14 years after the initiation of systemic immunosuppression therapies.[18][19][18] [19][19]

Epidemiology

Porokeratosis is an uncommon diagnosis and epidemiology depends heavily on the clinical variant. DSAP occurs on sun-exposed areas, DSP and EDP distribution in generalized, porokeratosis of Mibelli and linear subtypes are present in limbs, while punctate is seen in palms and soles.[20]  It is most commonly in the fifth decade of life but can occur at any age and has similar frequencies in males and females.[2] Although primarily seen in adults, porokeratosis has also been reported in the literature among young children.[21] [21] The increased occurrence of disseminated superficial actinic porokeratosis on sun-exposed skin likely indicates that UV light is a risk factor.[22]

The eruptive form of porokeratosis correlates with immune suppression, transplantation patients, inflammatory states, and malignancy.[4] Porokeratosis will progress to nonmelanoma skin cancer in 6.9% to 30% of cases, most frequently squamous cell carcinoma and less frequently basal cell carcinoma.[6] One study of 281 patients with porokeratosis found risks for malignant transformation in patients with linear porokeratosis to be 19%, porokeratosis plantaris, palmaris, et disseminate at 10%, porokeratosis of Mibelli of any size at 8%, and disseminated superficial actinic porokeratosis at 3%.[23] [20]

It is important to note that porokeratosis lesions do not immediately become cancerous; the average period before it transforms into a cancerous lesion is about 36 years.[3] Although porokeratosis is usually an acquired disease, there is often a familial predisposition that could signify a hereditary component.[5] [10]

Pathophysiology

Porokeratosis is an entity that results from the disordered progression of epidermal cells.[24] The development of this entity can be related to sun exposure. In areas with no or limited sun exposure, repeated minor frictional trauma due to tight clothing may cause the entity, as in genitourinary porokeratosis.[1] 

There is a reported association with overexpression of p53, and occasionally, there can be an expansion of a clone of abnormal epidermal keratinocytes.[5][6] Porokeratosis has the possibility of malignant transformation into squamous cell carcinoma or basal cell carcinoma.[5]

Histopathology

The distinctive histopathologic feature of porokeratosis is a cornoid lamella, a column of tightly fitted parakeratotic cells.[2][3] The column of parakeratosis will occur over the epidermis with an absent granular layer and dyskeratotic cells in the upper spinous zone.[1] This feature is usually present at the elevated border of the lesion.[1] Although it was once thought pathognomonic of porokeratosis, the feature has presented in other conditions.[24] Cornoid lamellation reflects a disordered progression of epidermal cells.[24] In follicular porokeratosis, the cornoid lamella can involve the follicular infundibulum.[25]

History and Physical

Porokeratosis presents as keratotic papules or annular plaques that expand centrifugally with an elevated keratotic border.[1] Centrally, the lesion can appear slightly atrophic.[1] The lesions can present with pruritus and may be present for several years before diagnosis.[1] Disseminated nodules present as pink to brown papules and macules with raised borders.[4] 

Porokeratosis most commonly occurs in the limbs and trunk but can occur in the trunk, face, genitourinary region, and scrotum.[25] However, porokeratosis as an entity has a broad spectrum of presentations, including large destructive lesions and the involvement of burn scars.[6] Careful attention must be paid to relatively large porokeratosis lesions, located on sun-exposed areas on the extremities, and lesions that have a long duration since onset, as these are all risk factors for malignant transformation.[3] 

Evaluation

Evaluation of porokeratosis is best with a biopsy of the elevated border.[1] Biopsy in this area will show the cornoid lamella and will be diagnostic. Dermoscopy can also be helpful for diagnosis. Dermoscopy of lesions shows central brown pigmentation with blue-gray dots surrounded by a single hypopigmented band with a white track at the periphery.[1] Despite the relative rarity of porokeratosis, especially some subtypes like genitourinary porokeratosis, the diagnosis should be kept in mind due to the risk of malignant degeneration.[6]

Treatment / Management

Multiple therapies have been described for the different clinical variations of porokeratosis, including topical, systemic, and surgical options. However, because porokeratosis has not been studied in randomized controlled trials, there are no international guidelines on treatment standards.[7] Various forms of porokeratosis have been effectively treated as follows:

• Classical porokeratosis of Mibelli: Most successfully treated with imiquimod cream [7]
• DSAP
  • Diclofenac 3% gel: rated 4/10 efficacy with minimal adverse effects. [26] [27]
  • Radiotherapy: at least 50% effectiveness, side effects include pigmentation disorders, alopecia, skin atrophy, telangiectasia, fibrosis, and secondary skin malignancies.[28][29][30]
  • Vitamin D3 analogues proven effective: calcipotriol 0.005% twice daily, tacalcitol 0.002% or 0.004%, calcipotriol 0.005% / adapalene 0.1% gel, calcipotriol/ betamethasone gel, and CO2 laser with tacalcitol 0.002% ointment.[20]
  • Laser therapy and cryotherapy have shown excellent results. [20]
  • Topical 2% levostatin: a 2023 randomized controlled trial showed excellent results and suggested levostatin cream as a primary treatment option.[31]
• Linear porokeratosis: Responds well to topical or systemic retinoids [7]
• DSP: treatment is similar to DSAP with the exclusion of topical statin. Small reports have also studied the efficacy of dimethyl sulphoxide (DMSO)[32], oral tofacitinib[33], and a traditional Chinese herbal medicine called Huang-Lian-Jie-Tang.[34] All these medications were proven to provide relief of pruritis in small sample-size studies.
• Eruptive Disseminated porokeratosis (EDP): a subvariant of DSP, tends to subside spontaneously within a month. [35]
• Punctate porokeratosis: data on treatment is scarce, but systemic retinoids such as isotretinoin, etrenitate, and acitretin are the medications with the best-documented effect.[20]

Surgical interventions, such as sharp excision, curettage and electrodesiccation are options for treatment in areas where topical agents are challenging to use or contraindicated.[7] 

In general, patients with a few, small lesions who would like a quick resolution and can tolerate the potential for potential aesthetic complications are good candidates for surgical or laser modalities. Patients with multiple, large lesions are not good surgical candidates and would be best managed by topical pharmacologic therapies. Lastly, patients who are hesitant to pursue surgical or intensive topical pharmacologic therapy are best managed by topical keratolytic agents.

Differential Diagnosis

Clinically, porokeratosis can resemble:

• Psoriasis
• Lichen simplex chronicus
• Hypertrophic lichen planus
• Tuberculosis of the skin
• Bowen disease
• Candidiasis
• Irritants
• Allergic contact dermatitis [1]

Prognosis

Porokeratosis will remain indefinitely without medical or surgical intervention, and spontaneous regression of these lesions is extremely rare.[18] Porokeratosis is a premalignant condition[1]; however, all types of porokeratosis can undergo malignant transformation to nonmelanoma skin cancer at a rate of 6.9% to 30%.[2][6] Most commonly, porokeratosis lesions transform into squamous cell carcinoma; less frequently, they transform into basal cell carcinoma. If the lesions have not undergone a malignant transformation, excision is curative.

Linear porokeratosis and giant porokeratosis are the variants that are most susceptible to malignant transformation. Malignant transformation is rare in disseminated superficial actinic porokeratosis.[36]

Complications

Complications of porokeratosis are based on treatment selection. General complications of surgical excision include infection, bleeding, and scarring. Topical treatments can irritate the skin or cause skin atrophy, pruritus, xerosis, or pigmentation changes. Complications can also be related to a lack of early diagnosis with a biopsy and a lack of treatment, leading to the potential for malignant transformation. 

Consultations

Patients with porokeratosis may consult with the following:

• Dermatologists
• Dermatology nurses
• Mohs surgeons
• Plastic surgeons

Deterrence and Patient Education

Porokeratosis is a precancerous skin lesion that presents with small, callus-like raised lesions (keratotic papules) or flat, round-shaped lesions (annular plaques) with an elevated border. These lesions become cancerous anywhere from 6.9% to 30% of the time, based on current research, and most frequently transform into squamous cell carcinoma.

Porokeratosis is often found in sun-exposed areas and is noted in the fifth decade of life. Interestingly, several different clinical variants of porokeratosis exist, but the exact etiology and pathology of these lesions remain unclear. Of all the clinical variants, linear and giant porokeratosis have the worst prognosis, as they are most likely to undergo malignant transformation. On the other hand, malignant transformation is rare in disseminated superficial actinic porokeratosis. There may be a multifactorial cause of Porokeratosis with possible etiologies, including UV light, trauma, genetics, infectious agents, and immunosuppression.

In addition to clinical evaluation, the best method for definitive diagnosis is a biopsy of the elevated border. Biopsy in this area will show the cornoid lamella and will be diagnostic. Clinically, porokeratosis can resemble other skin conditions, such as psoriasis, lichen simplex chronicus, hypertrophic lichen planus, tuberculosis of the skin, Bowen disease, candidiasis, irritants, and allergic contact dermatitis.

Multiple therapies are described for porokeratosis, including topical, systemic, and surgical options. Patients should be evaluated annually to monitor for signs and symptoms of malignancy to reduce the risk of malignant transformation of porokeratosis. In addition, providers will screen for underlying systemic immunosuppressive disorders and re-educate sun protection.

If the lesions carry several risk factors for malignant transformation, such as large, numerous, and long-standing lesions, bi-annual follow-up visits should be scheduled. If a porokeratosis lesion begins to exhibit clinical features concerning for a malignancy, a patient sees a provider immediately for excision or biopsy.

Pearls and Other Issues

• Histologically, the hallmark of porokeratosis is a cornoid lamella, a column of tightly fitted parakeratotic cells.[3]
• Porokeratosis presents as keratotic papules or annular plaques that expand centrifugally with an elevated keratotic border.[1] Dermoscopy of lesions shows central brown pigmentation with blue-gray dots surrounded by a single hypopigmented band with a white track at the periphery.[1]
• There are many variants of porokeratosis.[2]
• Porokeratosis can undergo malignant transformation to squamous cell carcinoma and basal cell carcinoma.[6]
• Evaluation of porokeratosis is best done with a biopsy of the elevated border.[1]
• Multiple therapies are described for porokeratosis, including topical, systemic, and surgical options. However, because porokeratosis has not been studied in randomized controlled trials, there are no international guidelines on treatment standards.[7]
• Patients treated for porokeratosis should be advised to use sun protection, avoid excessive sunlight exposure, and undergo periodic examinations by a dermatologist to monitor for recurrence or malignant transformation.[2]

Enhancing Healthcare Team Outcomes

Dermatologists and other clinicians should work closely with pathologists to ensure porokeratosis lesions are evaluated for malignant transformation.[2] Dermatologists and dermatology specialty nurses should periodically follow up with patients to monitor for recurrence.[2] An interprofessional team approach to follow-up will provide the best patient outcomes.