Cutis

The Diagnosis: Collision Tumor

Excisional biopsy and histopathological examination demonstrated a collision tumor composed of a benign intradermal melanocytic nevus, tumor of follicular infundibulum, and an underlying sclerosing epithelial neoplasm, with a differential diagnosis of desmoplastic trichoepithelioma, morpheaform basal cell carcinoma, and microcystic adnexal carcinoma (Figure).

Common acquired melanocytic nevus presents clinically as a macule, papule, or nodule with smooth regular borders. The pigmented variant displays an evenly distributed pigment on the lesion. Intradermal melanocytic nevus often presents as a flesh-colored nodule, as in our case. Histopathologically, benign intradermal nevus typically is composed of a proliferation of melanocytes that exhibit dispersion as they go deeper in the dermis and maturation that manifests as melanocytes becoming smaller and more spindled in the deeper portions of the lesion.¹ These 2 characteristics plus the bland cytology seen in the present case confirm the benign characteristic of this lesion (Figure, B).

In addition to the benign intradermal melanocytic nevus, an adjacent tumor of follicular infundibulum was noted. Tumor of follicular infundibulum is a rare adnexal tumor. It occurs frequently on the head and neck and shows some female predominance.^2,3 Multiple lesions and eruptive lesions are rare forms that also have been reported.⁴ Histopathologically, the tumor demonstrates an epithelial plate that is present in the papillary dermis and is connected to the epidermis at multiple points with attachment to the follicular outer root sheath. Peripheral palisading is characteristically present above an eosinophilic basement membrane (Figure, A). Rare reports have documented sebaceous and eccrine differentiation.^5,6

Tumor of follicular infundibulum has been reported to be associated with other tumors. Organoid nevus (nevus sebaceous), trichilemmal tumor, and fibroma have been reported to occur as a collision tumor with tumor of follicular infundibulum. An association with Cowden disease also has been described.⁷ Biopsies that represent partial samples should be interpreted cautiously, as step sections can reveal basal cell carcinoma.

The term sclerosing epithelial neoplasm describes tumors that share a paisley tielike epithelial pattern and sclerotic stroma. Small specimens often require clinicopathologic correlation (Figure, C). The differential diagnosis includes morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and microcystic adnexal carcinoma. A panel of stains using Ber-EP4, PHLDA1, cytokeratin 15, and cytokeratin 19 has been proposed to help differentiate these entities.⁸ CD34 and cytokeratin 20 also have been used with varying success in small specimens.^9,10

The Diagnosis: Collision Tumor

Excisional biopsy and histopathological examination demonstrated a collision tumor composed of a benign intradermal melanocytic nevus, tumor of follicular infundibulum, and an underlying sclerosing epithelial neoplasm, with a differential diagnosis of desmoplastic trichoepithelioma, morpheaform basal cell carcinoma, and microcystic adnexal carcinoma (Figure).

Common acquired melanocytic nevus presents clinically as a macule, papule, or nodule with smooth regular borders. The pigmented variant displays an evenly distributed pigment on the lesion. Intradermal melanocytic nevus often presents as a flesh-colored nodule, as in our case. Histopathologically, benign intradermal nevus typically is composed of a proliferation of melanocytes that exhibit dispersion as they go deeper in the dermis and maturation that manifests as melanocytes becoming smaller and more spindled in the deeper portions of the lesion.¹ These 2 characteristics plus the bland cytology seen in the present case confirm the benign characteristic of this lesion (Figure, B).

In addition to the benign intradermal melanocytic nevus, an adjacent tumor of follicular infundibulum was noted. Tumor of follicular infundibulum is a rare adnexal tumor. It occurs frequently on the head and neck and shows some female predominance.^2,3 Multiple lesions and eruptive lesions are rare forms that also have been reported.⁴ Histopathologically, the tumor demonstrates an epithelial plate that is present in the papillary dermis and is connected to the epidermis at multiple points with attachment to the follicular outer root sheath. Peripheral palisading is characteristically present above an eosinophilic basement membrane (Figure, A). Rare reports have documented sebaceous and eccrine differentiation.^5,6

Tumor of follicular infundibulum has been reported to be associated with other tumors. Organoid nevus (nevus sebaceous), trichilemmal tumor, and fibroma have been reported to occur as a collision tumor with tumor of follicular infundibulum. An association with Cowden disease also has been described.⁷ Biopsies that represent partial samples should be interpreted cautiously, as step sections can reveal basal cell carcinoma.

The term sclerosing epithelial neoplasm describes tumors that share a paisley tielike epithelial pattern and sclerotic stroma. Small specimens often require clinicopathologic correlation (Figure, C). The differential diagnosis includes morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and microcystic adnexal carcinoma. A panel of stains using Ber-EP4, PHLDA1, cytokeratin 15, and cytokeratin 19 has been proposed to help differentiate these entities.⁸ CD34 and cytokeratin 20 also have been used with varying success in small specimens.^9,10

The Diagnosis: Collision Tumor

Excisional biopsy and histopathological examination demonstrated a collision tumor composed of a benign intradermal melanocytic nevus, tumor of follicular infundibulum, and an underlying sclerosing epithelial neoplasm, with a differential diagnosis of desmoplastic trichoepithelioma, morpheaform basal cell carcinoma, and microcystic adnexal carcinoma (Figure).

Common acquired melanocytic nevus presents clinically as a macule, papule, or nodule with smooth regular borders. The pigmented variant displays an evenly distributed pigment on the lesion. Intradermal melanocytic nevus often presents as a flesh-colored nodule, as in our case. Histopathologically, benign intradermal nevus typically is composed of a proliferation of melanocytes that exhibit dispersion as they go deeper in the dermis and maturation that manifests as melanocytes becoming smaller and more spindled in the deeper portions of the lesion.¹ These 2 characteristics plus the bland cytology seen in the present case confirm the benign characteristic of this lesion (Figure, B).

In addition to the benign intradermal melanocytic nevus, an adjacent tumor of follicular infundibulum was noted. Tumor of follicular infundibulum is a rare adnexal tumor. It occurs frequently on the head and neck and shows some female predominance.^2,3 Multiple lesions and eruptive lesions are rare forms that also have been reported.⁴ Histopathologically, the tumor demonstrates an epithelial plate that is present in the papillary dermis and is connected to the epidermis at multiple points with attachment to the follicular outer root sheath. Peripheral palisading is characteristically present above an eosinophilic basement membrane (Figure, A). Rare reports have documented sebaceous and eccrine differentiation.^5,6

Tumor of follicular infundibulum has been reported to be associated with other tumors. Organoid nevus (nevus sebaceous), trichilemmal tumor, and fibroma have been reported to occur as a collision tumor with tumor of follicular infundibulum. An association with Cowden disease also has been described.⁷ Biopsies that represent partial samples should be interpreted cautiously, as step sections can reveal basal cell carcinoma.

The term sclerosing epithelial neoplasm describes tumors that share a paisley tielike epithelial pattern and sclerotic stroma. Small specimens often require clinicopathologic correlation (Figure, C). The differential diagnosis includes morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and microcystic adnexal carcinoma. A panel of stains using Ber-EP4, PHLDA1, cytokeratin 15, and cytokeratin 19 has been proposed to help differentiate these entities.⁸ CD34 and cytokeratin 20 also have been used with varying success in small specimens.^9,10

The Diagnosis: PELVIS Syndrome

Infantile hemangiomas (IHs) are present in up to 10% of infants by 1 year of age and are most commonly located on the face and upper extremities. Less than 10% of IHs develop in the perineum.¹ Perineal IHs are benign tumors of the vascular endothelium that present as plaques and commonly are accompanied by painful ulcerations. Ulceration is more common in the diaper area secondary to irritation from urine, stool, and friction.² Although most IHs are benign isolated findings, facial IHs have been associated with several syndromes including Sturge-Weber and PHACE (posterior fossa brain malformations, hemangiomas, arterial anomalies, cardiac anomalies and coarctation of the aorta, and eye and endocrine abnormalities) syndromes.³ Researchers also have identified an association between lumbosacral IHs and spinal dysraphism (tethered spinal cord).⁴

A smaller number of studies have investigated congenital anomalies related to perineal IH,^1,5 specifically PELVIS syndrome. The acronym PELVIS has been used to describe a syndrome of congenital malformations including perineal hemangioma, external genital malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag.¹ An alternative description of similar findings is LUMBAR (lower body hemangioma and other cutaneous defects; urogenital anomalies, ulceration; myelopathy; bony deformities; anorectal malformations, arterial anomalies; and renal anomalies).⁵ Researchers have suggested that both of these acronyms describe the same syndrome, and it is common for the syndrome to be incomplete.⁶ One study (N=11) found that perineal hemangiomas are most commonly associated with anal malformations (8 patients), followed by urinary tract abnormalities (7 patients) and malformation of the external genitalia (7 patients). A skin tag was present in 5 patients.¹ The pathogenesis of PELVIS syndrome is unknown.

When an infant presents with a perineal hemangioma and physical examination suggests PELVIS syndrome, imaging should be performed to evaluate for other anomalies. Before 4 months of age, ultrasound should be utilized to investigate the presence of reno-genitourinary or spinal malformations. Magnetic resonance imaging is the preferred imaging modality in children older than 4 months.⁷ Management of PELVIS syndrome requires a multidisciplinary approach and early recognition of the full extent of congenital malformations. Pediatric dermatologists, urologists, endocrinologists, and neonatologists have a role in its diagnosis and treatment.

The Diagnosis: PELVIS Syndrome

Infantile hemangiomas (IHs) are present in up to 10% of infants by 1 year of age and are most commonly located on the face and upper extremities. Less than 10% of IHs develop in the perineum.¹ Perineal IHs are benign tumors of the vascular endothelium that present as plaques and commonly are accompanied by painful ulcerations. Ulceration is more common in the diaper area secondary to irritation from urine, stool, and friction.² Although most IHs are benign isolated findings, facial IHs have been associated with several syndromes including Sturge-Weber and PHACE (posterior fossa brain malformations, hemangiomas, arterial anomalies, cardiac anomalies and coarctation of the aorta, and eye and endocrine abnormalities) syndromes.³ Researchers also have identified an association between lumbosacral IHs and spinal dysraphism (tethered spinal cord).⁴

A smaller number of studies have investigated congenital anomalies related to perineal IH,^1,5 specifically PELVIS syndrome. The acronym PELVIS has been used to describe a syndrome of congenital malformations including perineal hemangioma, external genital malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag.¹ An alternative description of similar findings is LUMBAR (lower body hemangioma and other cutaneous defects; urogenital anomalies, ulceration; myelopathy; bony deformities; anorectal malformations, arterial anomalies; and renal anomalies).⁵ Researchers have suggested that both of these acronyms describe the same syndrome, and it is common for the syndrome to be incomplete.⁶ One study (N=11) found that perineal hemangiomas are most commonly associated with anal malformations (8 patients), followed by urinary tract abnormalities (7 patients) and malformation of the external genitalia (7 patients). A skin tag was present in 5 patients.¹ The pathogenesis of PELVIS syndrome is unknown.

When an infant presents with a perineal hemangioma and physical examination suggests PELVIS syndrome, imaging should be performed to evaluate for other anomalies. Before 4 months of age, ultrasound should be utilized to investigate the presence of reno-genitourinary or spinal malformations. Magnetic resonance imaging is the preferred imaging modality in children older than 4 months.⁷ Management of PELVIS syndrome requires a multidisciplinary approach and early recognition of the full extent of congenital malformations. Pediatric dermatologists, urologists, endocrinologists, and neonatologists have a role in its diagnosis and treatment.

The Diagnosis: PELVIS Syndrome

Infantile hemangiomas (IHs) are present in up to 10% of infants by 1 year of age and are most commonly located on the face and upper extremities. Less than 10% of IHs develop in the perineum.¹ Perineal IHs are benign tumors of the vascular endothelium that present as plaques and commonly are accompanied by painful ulcerations. Ulceration is more common in the diaper area secondary to irritation from urine, stool, and friction.² Although most IHs are benign isolated findings, facial IHs have been associated with several syndromes including Sturge-Weber and PHACE (posterior fossa brain malformations, hemangiomas, arterial anomalies, cardiac anomalies and coarctation of the aorta, and eye and endocrine abnormalities) syndromes.³ Researchers also have identified an association between lumbosacral IHs and spinal dysraphism (tethered spinal cord).⁴

A smaller number of studies have investigated congenital anomalies related to perineal IH,^1,5 specifically PELVIS syndrome. The acronym PELVIS has been used to describe a syndrome of congenital malformations including perineal hemangioma, external genital malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag.¹ An alternative description of similar findings is LUMBAR (lower body hemangioma and other cutaneous defects; urogenital anomalies, ulceration; myelopathy; bony deformities; anorectal malformations, arterial anomalies; and renal anomalies).⁵ Researchers have suggested that both of these acronyms describe the same syndrome, and it is common for the syndrome to be incomplete.⁶ One study (N=11) found that perineal hemangiomas are most commonly associated with anal malformations (8 patients), followed by urinary tract abnormalities (7 patients) and malformation of the external genitalia (7 patients). A skin tag was present in 5 patients.¹ The pathogenesis of PELVIS syndrome is unknown.

When an infant presents with a perineal hemangioma and physical examination suggests PELVIS syndrome, imaging should be performed to evaluate for other anomalies. Before 4 months of age, ultrasound should be utilized to investigate the presence of reno-genitourinary or spinal malformations. Magnetic resonance imaging is the preferred imaging modality in children older than 4 months.⁷ Management of PELVIS syndrome requires a multidisciplinary approach and early recognition of the full extent of congenital malformations. Pediatric dermatologists, urologists, endocrinologists, and neonatologists have a role in its diagnosis and treatment.

Disseminated superficial actinic porokeratosis (DSAP) is a chronic condition characterized by numerous atrophic papules and patches with a distinctive peripheral keratotic ridge, typically found on sun-exposed areas.^1,2 Treatment of DSAP is warranted not only for cosmetic and symptomatic benefits but also to prevent malignant transformation.^3,4 Successful treatment of DSAP often is difficult and frequently requires the use of multiple modalities. Ingenol mebutate gel 0.05% is a topical medication primarily used for the treatment of actinic keratosis (AK) by inducing cell death.⁵ We report a case of DSAP treated effectively with ingenol mebutate gel 0.05%.

Case Report

A 37-year-old woman was referred to the dermatology department for counseling for pseudoxanthoma elasticum (PXE), which had been proven on biopsy by an outside dermatologist 2 years prior. Physical examination revealed yellow papules on the neck that were characteristic of PXE, but no lesions were noted on the arms or legs. The only other cutaneous finding was a soft nodule on the right hip consistent with a lipoma. The patient returned to our institution 6 years later with lesions on both lower legs. She reported that these lesions had been present for 3 years and were exacerbated by sun exposure. On physical examination, multiple scattered, erythematous, annular, scaling papules and plaques were noted on the bilateral legs. A biopsy showed the histopathologic findings of DSAP (Figure 1). The patient had no family history of DSAP or PXE.

To determine the best treatment modality, we treated 4 test areas on both upper and lower legs: one with trichloroacetic acid (TCA), one with cryotherapy, one with imiquimod cream 5%, and one with tretinoin cream 0.1%. The patient returned 4 weeks later and showed modest response to TCA, cryotherapy, and tretinoin cream. Because cryotherapy was determined to be most effective, 20 more lesions were frozen at that visit. Over the next 2 years, the patient was treated with TCA, imiquimod cream 5%, and tretinoin cream 0.1%, but all ultimately proved ineffective for DSAP.

The patient returned 2 years after treatment failure (age 47 years) and was prescribed ingenol mebutate gel 0.05% for 2 days over an area of 25 cm² on the right lower leg (Figure 2A). She returned for follow-up at days 3, 15, 30, and 60. At day 3, the patient developed an inflammatory response to the medication with moderate erythema and scaling of individual lesions. No vesiculation, pustulation, edema, or ulceration was exhibited (Figure 2B). At day 30, there was a marked reduction in scaling with some postinflammatory erythema (Figure 2C). At day 60, much of the erythema had faded and the scale remained notably reduced (Figure 2D).

Comment

Disseminated superficial actinic porokeratosis is the most common subtype of porokeratosis, a keratinization disorder. There are 6 subtypes of porokeratosis identified in the literature: DSAP, disseminated superficial porokeratosis, classic porokeratosis of Mibelli, porokeratosis plantaris palmaris et disseminata, linear porokeratosis, and punctate porokeratosis.⁶ Disseminated superficial actinic porokeratosis has a female predominance (1.8:1 ratio)⁷ and generally appears in the third or fourth decades of life. Clonal proliferations of atypical keratinocytes have been implicated in the etiology of DSAP; however, the exact pathogenesis is unclear. Risk factors for DSAP include genetic susceptibility (eg, autosomal-dominant inheritance pattern), exposure to UV radiation, and drug-related immunosuppression or immunodeficiency.⁷ Other proposed etiologic risk factors include trauma and infection.⁸ Clinical diagnosis of DSAP is confirmed by the histological presence of a cornoid lamella (a thin column ofparakeratotic cells), a thinning epidermis, an absent or thinned granular cell layer, and a prominent dermal lymphocytic infiltrate.^9,10

Disseminated superficial actinic porokeratosis clinically presents as small atrophic scaly papules and/or patches with raised peripheral ridges symmetrically dispersed on sun-exposed areas of the arms, legs, back, and shoulders. Although these lesions are extensive, they typically spare the mucous membranes, palms, and soles¹¹; only a small percentage of cases report facial lesions,¹² which often are asymptomatic but cosmetically bothersome. Additionally, approximately half of patients report symptoms of pruritus and/or stinging,¹³ thus treatment of DSAP is mainly indicated for symptomatic relief and cosmetic purposes. Malignant degeneration^14,15 occurs in approximately 7.5% to 11% of porokeratosis cases,^10,16 warranting treatment for preventative measures.

Management of DSAP is dependent on the extent of the disease and the level of concern for malignant transformation. Localized disease can be treated with cryotherapy, CO₂ laser, and/or ablative techniques (eg, excision, curettage, dermabrasion) with variable degrees of success but high risk for scarring.¹ More extensive disease requires treatment with topical retinoids, topical 5-fluorouracil, imiquimod cream 5%, diclofenac gel 3%, topical vitamin D₃ analogues, and photodynamic therapy.¹ Several other therapies have been reported in the literature with partial and/or complete success, including systemic retinoids (eg, acitretin), Q-switched ruby laser, Nd:YAG laser, fractional photothermolysis, Grenz rays, pulsed dye laser, fractional photothermolysis, topical corticosteroids, and fluor-hydroxy pulse peel.⁶ Although there is an extensive array of therapies for DSAP, treatment results are variable with mostly limited success. Successful treatment of DSAP is difficult and often requires the use of multiple modalities.

Ingenol mebutate is the active compound found in the sap of Euphorbia peplus used for the topical treatment of various skin conditions, including AKs.¹⁷ Ingenol mebutate gel 0.05% once daily for 2 days has been approved by the US Food and Drug Administration for the topical treatment of AKs. The mechanism of action of ingenol mebutate in AK therapy is not yet fully understood. In vivo and in vitro models have demonstrated both an induction of local lesion cell death and promotion of lesion-specific inflammatory response.¹⁸ When used in the treatment of AKs, ingenol mebutate gel 0.05% may cause a mild to moderate localized inflammatory response (eg, erythema, flaking/scaling, crusting, vesiculation/pustulation, erosion/ulceration, edema).

Our case is a rare report of successful treatment of DSAP with ingenol mebutate gel 0.05%. We found that treatment with ingenol mebutate gel 0.05% resulted in clinical improvement of DSAP lesions with minimal discomfort and good cosmetic response. This 2-day regimen is easy to use and patient friendly, improving medication compliance in such a cumbersome disease. We hope this case suggests that ingenol mebutate gel 0.05% could be a useful treatment alternative for DSAP, but future clinical studies should be conducted.

Disseminated superficial actinic porokeratosis (DSAP) is a chronic condition characterized by numerous atrophic papules and patches with a distinctive peripheral keratotic ridge, typically found on sun-exposed areas.^1,2 Treatment of DSAP is warranted not only for cosmetic and symptomatic benefits but also to prevent malignant transformation.^3,4 Successful treatment of DSAP often is difficult and frequently requires the use of multiple modalities. Ingenol mebutate gel 0.05% is a topical medication primarily used for the treatment of actinic keratosis (AK) by inducing cell death.⁵ We report a case of DSAP treated effectively with ingenol mebutate gel 0.05%.

Case Report

A 37-year-old woman was referred to the dermatology department for counseling for pseudoxanthoma elasticum (PXE), which had been proven on biopsy by an outside dermatologist 2 years prior. Physical examination revealed yellow papules on the neck that were characteristic of PXE, but no lesions were noted on the arms or legs. The only other cutaneous finding was a soft nodule on the right hip consistent with a lipoma. The patient returned to our institution 6 years later with lesions on both lower legs. She reported that these lesions had been present for 3 years and were exacerbated by sun exposure. On physical examination, multiple scattered, erythematous, annular, scaling papules and plaques were noted on the bilateral legs. A biopsy showed the histopathologic findings of DSAP (Figure 1). The patient had no family history of DSAP or PXE.

To determine the best treatment modality, we treated 4 test areas on both upper and lower legs: one with trichloroacetic acid (TCA), one with cryotherapy, one with imiquimod cream 5%, and one with tretinoin cream 0.1%. The patient returned 4 weeks later and showed modest response to TCA, cryotherapy, and tretinoin cream. Because cryotherapy was determined to be most effective, 20 more lesions were frozen at that visit. Over the next 2 years, the patient was treated with TCA, imiquimod cream 5%, and tretinoin cream 0.1%, but all ultimately proved ineffective for DSAP.

The patient returned 2 years after treatment failure (age 47 years) and was prescribed ingenol mebutate gel 0.05% for 2 days over an area of 25 cm² on the right lower leg (Figure 2A). She returned for follow-up at days 3, 15, 30, and 60. At day 3, the patient developed an inflammatory response to the medication with moderate erythema and scaling of individual lesions. No vesiculation, pustulation, edema, or ulceration was exhibited (Figure 2B). At day 30, there was a marked reduction in scaling with some postinflammatory erythema (Figure 2C). At day 60, much of the erythema had faded and the scale remained notably reduced (Figure 2D).

Comment

Disseminated superficial actinic porokeratosis is the most common subtype of porokeratosis, a keratinization disorder. There are 6 subtypes of porokeratosis identified in the literature: DSAP, disseminated superficial porokeratosis, classic porokeratosis of Mibelli, porokeratosis plantaris palmaris et disseminata, linear porokeratosis, and punctate porokeratosis.⁶ Disseminated superficial actinic porokeratosis has a female predominance (1.8:1 ratio)⁷ and generally appears in the third or fourth decades of life. Clonal proliferations of atypical keratinocytes have been implicated in the etiology of DSAP; however, the exact pathogenesis is unclear. Risk factors for DSAP include genetic susceptibility (eg, autosomal-dominant inheritance pattern), exposure to UV radiation, and drug-related immunosuppression or immunodeficiency.⁷ Other proposed etiologic risk factors include trauma and infection.⁸ Clinical diagnosis of DSAP is confirmed by the histological presence of a cornoid lamella (a thin column ofparakeratotic cells), a thinning epidermis, an absent or thinned granular cell layer, and a prominent dermal lymphocytic infiltrate.^9,10

Disseminated superficial actinic porokeratosis clinically presents as small atrophic scaly papules and/or patches with raised peripheral ridges symmetrically dispersed on sun-exposed areas of the arms, legs, back, and shoulders. Although these lesions are extensive, they typically spare the mucous membranes, palms, and soles¹¹; only a small percentage of cases report facial lesions,¹² which often are asymptomatic but cosmetically bothersome. Additionally, approximately half of patients report symptoms of pruritus and/or stinging,¹³ thus treatment of DSAP is mainly indicated for symptomatic relief and cosmetic purposes. Malignant degeneration^14,15 occurs in approximately 7.5% to 11% of porokeratosis cases,^10,16 warranting treatment for preventative measures.

Management of DSAP is dependent on the extent of the disease and the level of concern for malignant transformation. Localized disease can be treated with cryotherapy, CO₂ laser, and/or ablative techniques (eg, excision, curettage, dermabrasion) with variable degrees of success but high risk for scarring.¹ More extensive disease requires treatment with topical retinoids, topical 5-fluorouracil, imiquimod cream 5%, diclofenac gel 3%, topical vitamin D₃ analogues, and photodynamic therapy.¹ Several other therapies have been reported in the literature with partial and/or complete success, including systemic retinoids (eg, acitretin), Q-switched ruby laser, Nd:YAG laser, fractional photothermolysis, Grenz rays, pulsed dye laser, fractional photothermolysis, topical corticosteroids, and fluor-hydroxy pulse peel.⁶ Although there is an extensive array of therapies for DSAP, treatment results are variable with mostly limited success. Successful treatment of DSAP is difficult and often requires the use of multiple modalities.

Ingenol mebutate is the active compound found in the sap of Euphorbia peplus used for the topical treatment of various skin conditions, including AKs.¹⁷ Ingenol mebutate gel 0.05% once daily for 2 days has been approved by the US Food and Drug Administration for the topical treatment of AKs. The mechanism of action of ingenol mebutate in AK therapy is not yet fully understood. In vivo and in vitro models have demonstrated both an induction of local lesion cell death and promotion of lesion-specific inflammatory response.¹⁸ When used in the treatment of AKs, ingenol mebutate gel 0.05% may cause a mild to moderate localized inflammatory response (eg, erythema, flaking/scaling, crusting, vesiculation/pustulation, erosion/ulceration, edema).

Our case is a rare report of successful treatment of DSAP with ingenol mebutate gel 0.05%. We found that treatment with ingenol mebutate gel 0.05% resulted in clinical improvement of DSAP lesions with minimal discomfort and good cosmetic response. This 2-day regimen is easy to use and patient friendly, improving medication compliance in such a cumbersome disease. We hope this case suggests that ingenol mebutate gel 0.05% could be a useful treatment alternative for DSAP, but future clinical studies should be conducted.

Disseminated superficial actinic porokeratosis (DSAP) is a chronic condition characterized by numerous atrophic papules and patches with a distinctive peripheral keratotic ridge, typically found on sun-exposed areas.^1,2 Treatment of DSAP is warranted not only for cosmetic and symptomatic benefits but also to prevent malignant transformation.^3,4 Successful treatment of DSAP often is difficult and frequently requires the use of multiple modalities. Ingenol mebutate gel 0.05% is a topical medication primarily used for the treatment of actinic keratosis (AK) by inducing cell death.⁵ We report a case of DSAP treated effectively with ingenol mebutate gel 0.05%.

Case Report

A 37-year-old woman was referred to the dermatology department for counseling for pseudoxanthoma elasticum (PXE), which had been proven on biopsy by an outside dermatologist 2 years prior. Physical examination revealed yellow papules on the neck that were characteristic of PXE, but no lesions were noted on the arms or legs. The only other cutaneous finding was a soft nodule on the right hip consistent with a lipoma. The patient returned to our institution 6 years later with lesions on both lower legs. She reported that these lesions had been present for 3 years and were exacerbated by sun exposure. On physical examination, multiple scattered, erythematous, annular, scaling papules and plaques were noted on the bilateral legs. A biopsy showed the histopathologic findings of DSAP (Figure 1). The patient had no family history of DSAP or PXE.

To determine the best treatment modality, we treated 4 test areas on both upper and lower legs: one with trichloroacetic acid (TCA), one with cryotherapy, one with imiquimod cream 5%, and one with tretinoin cream 0.1%. The patient returned 4 weeks later and showed modest response to TCA, cryotherapy, and tretinoin cream. Because cryotherapy was determined to be most effective, 20 more lesions were frozen at that visit. Over the next 2 years, the patient was treated with TCA, imiquimod cream 5%, and tretinoin cream 0.1%, but all ultimately proved ineffective for DSAP.

The patient returned 2 years after treatment failure (age 47 years) and was prescribed ingenol mebutate gel 0.05% for 2 days over an area of 25 cm² on the right lower leg (Figure 2A). She returned for follow-up at days 3, 15, 30, and 60. At day 3, the patient developed an inflammatory response to the medication with moderate erythema and scaling of individual lesions. No vesiculation, pustulation, edema, or ulceration was exhibited (Figure 2B). At day 30, there was a marked reduction in scaling with some postinflammatory erythema (Figure 2C). At day 60, much of the erythema had faded and the scale remained notably reduced (Figure 2D).

Comment

Disseminated superficial actinic porokeratosis is the most common subtype of porokeratosis, a keratinization disorder. There are 6 subtypes of porokeratosis identified in the literature: DSAP, disseminated superficial porokeratosis, classic porokeratosis of Mibelli, porokeratosis plantaris palmaris et disseminata, linear porokeratosis, and punctate porokeratosis.⁶ Disseminated superficial actinic porokeratosis has a female predominance (1.8:1 ratio)⁷ and generally appears in the third or fourth decades of life. Clonal proliferations of atypical keratinocytes have been implicated in the etiology of DSAP; however, the exact pathogenesis is unclear. Risk factors for DSAP include genetic susceptibility (eg, autosomal-dominant inheritance pattern), exposure to UV radiation, and drug-related immunosuppression or immunodeficiency.⁷ Other proposed etiologic risk factors include trauma and infection.⁸ Clinical diagnosis of DSAP is confirmed by the histological presence of a cornoid lamella (a thin column ofparakeratotic cells), a thinning epidermis, an absent or thinned granular cell layer, and a prominent dermal lymphocytic infiltrate.^9,10

Disseminated superficial actinic porokeratosis clinically presents as small atrophic scaly papules and/or patches with raised peripheral ridges symmetrically dispersed on sun-exposed areas of the arms, legs, back, and shoulders. Although these lesions are extensive, they typically spare the mucous membranes, palms, and soles¹¹; only a small percentage of cases report facial lesions,¹² which often are asymptomatic but cosmetically bothersome. Additionally, approximately half of patients report symptoms of pruritus and/or stinging,¹³ thus treatment of DSAP is mainly indicated for symptomatic relief and cosmetic purposes. Malignant degeneration^14,15 occurs in approximately 7.5% to 11% of porokeratosis cases,^10,16 warranting treatment for preventative measures.

Management of DSAP is dependent on the extent of the disease and the level of concern for malignant transformation. Localized disease can be treated with cryotherapy, CO₂ laser, and/or ablative techniques (eg, excision, curettage, dermabrasion) with variable degrees of success but high risk for scarring.¹ More extensive disease requires treatment with topical retinoids, topical 5-fluorouracil, imiquimod cream 5%, diclofenac gel 3%, topical vitamin D₃ analogues, and photodynamic therapy.¹ Several other therapies have been reported in the literature with partial and/or complete success, including systemic retinoids (eg, acitretin), Q-switched ruby laser, Nd:YAG laser, fractional photothermolysis, Grenz rays, pulsed dye laser, fractional photothermolysis, topical corticosteroids, and fluor-hydroxy pulse peel.⁶ Although there is an extensive array of therapies for DSAP, treatment results are variable with mostly limited success. Successful treatment of DSAP is difficult and often requires the use of multiple modalities.

Ingenol mebutate is the active compound found in the sap of Euphorbia peplus used for the topical treatment of various skin conditions, including AKs.¹⁷ Ingenol mebutate gel 0.05% once daily for 2 days has been approved by the US Food and Drug Administration for the topical treatment of AKs. The mechanism of action of ingenol mebutate in AK therapy is not yet fully understood. In vivo and in vitro models have demonstrated both an induction of local lesion cell death and promotion of lesion-specific inflammatory response.¹⁸ When used in the treatment of AKs, ingenol mebutate gel 0.05% may cause a mild to moderate localized inflammatory response (eg, erythema, flaking/scaling, crusting, vesiculation/pustulation, erosion/ulceration, edema).

Our case is a rare report of successful treatment of DSAP with ingenol mebutate gel 0.05%. We found that treatment with ingenol mebutate gel 0.05% resulted in clinical improvement of DSAP lesions with minimal discomfort and good cosmetic response. This 2-day regimen is easy to use and patient friendly, improving medication compliance in such a cumbersome disease. We hope this case suggests that ingenol mebutate gel 0.05% could be a useful treatment alternative for DSAP, but future clinical studies should be conducted.

Myth: Psoriasis Therapies Can Cause Suicidal Ideation in Psoriasis Patients

Psoriasis takes a toll on patients, both physically and emotionally. Depression is one of the comorbidities of psoriasis due to biological changes that cause psoriasis as well as the stigma of visible psoriasis. Severe depression and suicidal ideation have been perceived to be features of life-threatening medical disorders, but dermatologists need to be aware of the relationship between depressive symptoms, suicidal ideation, and psoriasis severity.

A 2010 United Kingdom study of 916,948 patients with mild psoriasis, severe psoriasis, or controls without psoriasis indicated that patients with psoriasis have an increased risk for depression, anxiety, and suicidality. The relative risk of these outcomes is elevated in younger patients with psoriasis, with the greatest relative risk being for depression in patients with severe psoriasis.

Kimball et al conducted a study in the United States of 7404 patients with psoriasis and 37,020 controls without psoriasis (age, <18 years). They reported that pediatric patients with psoriasis were significantly more at risk of developing psychiatric disorders versus controls (P=.0001), especially depression (P=.0036) and anxiety (P=.0048).

In February 2017, the US Food and Drug Administration (FDA) announced approval of brodalumab for use in adults with moderate to severe plaque psoriasis. It is intended for patients who are candidates for systemic therapy or phototherapy but have failed to respond or have stopped responding to other systemic therapies. Lebwohl et al published the results of the phase 3 clinical trials, which showed that brodalumab was highly effective in reducing plaque psoriasis, even compared to ustekinumab. In fact, psoriasis area and severity index scores of 100 were significantly higher in the brodalumab 210-mg group versus ustekinumab group by week 12 (P<.001).

However, the approval is accompanied with a strict warning from the FDA and tightly regulated access to the drug, as suicidal ideation and behavior, including 4 suicides, occurred in patients treated with brodalumab during clinical trials, particularly patients with a history of depression or suicidality. According to the FDA, "[a] causal association between treatment with [brodalumab] and increased risk of suicidal ideation and behavior has not been established." The label includes a black box warning and the drug will only be available through a restricted Risk Evaluation and Mitigation Strategy program, which has the following requirements from the FDA:

• Prescribers must be certified with the program and counsel patients about this risk. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate.
• Patients must sign a Patient-Prescriber Agreement Form and be made aware of the need to seek medical attention should they experience new or worsening suicidal thoughts or behavior, feelings of depression, anxiety, or other mood changes.
• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive the drug.

A medication guide is available for patients to inform them of the risk for suicidal ideation and behavior. The benefit of treatment must be weighed carefully against the seriousness of the risks associated with use.

Regardless of the therapy prescribed, dermatologists should be aware of the symptoms of depression. The National Psoriasis Foundation suggests you ask patients how they dress: Do they always wear long-sleeved shirts when they leave the house? Do they wear black? These questions can help determine if patients feel socially isolated or stigmatized by the disease. The National Psoriasis Foundation offers a Patient Navigation Center to help patients find a psychologist who specializes in issues related to psoriatic disease. Antidepressants and seeing a mental health professional can help, but ultimately taking control of the disease is the best way to improve depression.

Expert Commentary

According to the prescribing information for brodalumab, "Eight of the 10 subjects who attempted or completed suicide had a history of depression and/or suicidal ideation or behavior." Thus, 80% of these cases were at risk even before receiving 1 injection of brodalumab. Long-term registries will determine if there is truly an increased risk for suicidal ideation or behavior when taking brodalumab. 

Brodalumab will be commercially available around the fall 2017. Before prescribing brodalumab, I will counsel patients about this potential increased risk of suicidal ideation or behavior as noted in the prescribing information, but I will tell them that a true risk has not yet been determined in long-term registries. I will mention to patients that if they really do feel depressed or experience suicidal ideation or behavior after starting brodalumab, they should stop taking brodalumab and contact me or a mental health professional.

—Jashin J. Wu, MD (Los Angeles, California)

Myth: Psoriasis Therapies Can Cause Suicidal Ideation in Psoriasis Patients

Psoriasis takes a toll on patients, both physically and emotionally. Depression is one of the comorbidities of psoriasis due to biological changes that cause psoriasis as well as the stigma of visible psoriasis. Severe depression and suicidal ideation have been perceived to be features of life-threatening medical disorders, but dermatologists need to be aware of the relationship between depressive symptoms, suicidal ideation, and psoriasis severity.

A 2010 United Kingdom study of 916,948 patients with mild psoriasis, severe psoriasis, or controls without psoriasis indicated that patients with psoriasis have an increased risk for depression, anxiety, and suicidality. The relative risk of these outcomes is elevated in younger patients with psoriasis, with the greatest relative risk being for depression in patients with severe psoriasis.

Kimball et al conducted a study in the United States of 7404 patients with psoriasis and 37,020 controls without psoriasis (age, <18 years). They reported that pediatric patients with psoriasis were significantly more at risk of developing psychiatric disorders versus controls (P=.0001), especially depression (P=.0036) and anxiety (P=.0048).

In February 2017, the US Food and Drug Administration (FDA) announced approval of brodalumab for use in adults with moderate to severe plaque psoriasis. It is intended for patients who are candidates for systemic therapy or phototherapy but have failed to respond or have stopped responding to other systemic therapies. Lebwohl et al published the results of the phase 3 clinical trials, which showed that brodalumab was highly effective in reducing plaque psoriasis, even compared to ustekinumab. In fact, psoriasis area and severity index scores of 100 were significantly higher in the brodalumab 210-mg group versus ustekinumab group by week 12 (P<.001).

However, the approval is accompanied with a strict warning from the FDA and tightly regulated access to the drug, as suicidal ideation and behavior, including 4 suicides, occurred in patients treated with brodalumab during clinical trials, particularly patients with a history of depression or suicidality. According to the FDA, "[a] causal association between treatment with [brodalumab] and increased risk of suicidal ideation and behavior has not been established." The label includes a black box warning and the drug will only be available through a restricted Risk Evaluation and Mitigation Strategy program, which has the following requirements from the FDA:

• Prescribers must be certified with the program and counsel patients about this risk. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate.
• Patients must sign a Patient-Prescriber Agreement Form and be made aware of the need to seek medical attention should they experience new or worsening suicidal thoughts or behavior, feelings of depression, anxiety, or other mood changes.
• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive the drug.

A medication guide is available for patients to inform them of the risk for suicidal ideation and behavior. The benefit of treatment must be weighed carefully against the seriousness of the risks associated with use.

Regardless of the therapy prescribed, dermatologists should be aware of the symptoms of depression. The National Psoriasis Foundation suggests you ask patients how they dress: Do they always wear long-sleeved shirts when they leave the house? Do they wear black? These questions can help determine if patients feel socially isolated or stigmatized by the disease. The National Psoriasis Foundation offers a Patient Navigation Center to help patients find a psychologist who specializes in issues related to psoriatic disease. Antidepressants and seeing a mental health professional can help, but ultimately taking control of the disease is the best way to improve depression.

Expert Commentary

According to the prescribing information for brodalumab, "Eight of the 10 subjects who attempted or completed suicide had a history of depression and/or suicidal ideation or behavior." Thus, 80% of these cases were at risk even before receiving 1 injection of brodalumab. Long-term registries will determine if there is truly an increased risk for suicidal ideation or behavior when taking brodalumab. 

Brodalumab will be commercially available around the fall 2017. Before prescribing brodalumab, I will counsel patients about this potential increased risk of suicidal ideation or behavior as noted in the prescribing information, but I will tell them that a true risk has not yet been determined in long-term registries. I will mention to patients that if they really do feel depressed or experience suicidal ideation or behavior after starting brodalumab, they should stop taking brodalumab and contact me or a mental health professional.

—Jashin J. Wu, MD (Los Angeles, California)

Myth: Psoriasis Therapies Can Cause Suicidal Ideation in Psoriasis Patients

Psoriasis takes a toll on patients, both physically and emotionally. Depression is one of the comorbidities of psoriasis due to biological changes that cause psoriasis as well as the stigma of visible psoriasis. Severe depression and suicidal ideation have been perceived to be features of life-threatening medical disorders, but dermatologists need to be aware of the relationship between depressive symptoms, suicidal ideation, and psoriasis severity.

A 2010 United Kingdom study of 916,948 patients with mild psoriasis, severe psoriasis, or controls without psoriasis indicated that patients with psoriasis have an increased risk for depression, anxiety, and suicidality. The relative risk of these outcomes is elevated in younger patients with psoriasis, with the greatest relative risk being for depression in patients with severe psoriasis.

Kimball et al conducted a study in the United States of 7404 patients with psoriasis and 37,020 controls without psoriasis (age, <18 years). They reported that pediatric patients with psoriasis were significantly more at risk of developing psychiatric disorders versus controls (P=.0001), especially depression (P=.0036) and anxiety (P=.0048).

In February 2017, the US Food and Drug Administration (FDA) announced approval of brodalumab for use in adults with moderate to severe plaque psoriasis. It is intended for patients who are candidates for systemic therapy or phototherapy but have failed to respond or have stopped responding to other systemic therapies. Lebwohl et al published the results of the phase 3 clinical trials, which showed that brodalumab was highly effective in reducing plaque psoriasis, even compared to ustekinumab. In fact, psoriasis area and severity index scores of 100 were significantly higher in the brodalumab 210-mg group versus ustekinumab group by week 12 (P<.001).

However, the approval is accompanied with a strict warning from the FDA and tightly regulated access to the drug, as suicidal ideation and behavior, including 4 suicides, occurred in patients treated with brodalumab during clinical trials, particularly patients with a history of depression or suicidality. According to the FDA, "[a] causal association between treatment with [brodalumab] and increased risk of suicidal ideation and behavior has not been established." The label includes a black box warning and the drug will only be available through a restricted Risk Evaluation and Mitigation Strategy program, which has the following requirements from the FDA:

• Prescribers must be certified with the program and counsel patients about this risk. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate.
• Patients must sign a Patient-Prescriber Agreement Form and be made aware of the need to seek medical attention should they experience new or worsening suicidal thoughts or behavior, feelings of depression, anxiety, or other mood changes.
• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive the drug.

A medication guide is available for patients to inform them of the risk for suicidal ideation and behavior. The benefit of treatment must be weighed carefully against the seriousness of the risks associated with use.

Regardless of the therapy prescribed, dermatologists should be aware of the symptoms of depression. The National Psoriasis Foundation suggests you ask patients how they dress: Do they always wear long-sleeved shirts when they leave the house? Do they wear black? These questions can help determine if patients feel socially isolated or stigmatized by the disease. The National Psoriasis Foundation offers a Patient Navigation Center to help patients find a psychologist who specializes in issues related to psoriatic disease. Antidepressants and seeing a mental health professional can help, but ultimately taking control of the disease is the best way to improve depression.

Expert Commentary

According to the prescribing information for brodalumab, "Eight of the 10 subjects who attempted or completed suicide had a history of depression and/or suicidal ideation or behavior." Thus, 80% of these cases were at risk even before receiving 1 injection of brodalumab. Long-term registries will determine if there is truly an increased risk for suicidal ideation or behavior when taking brodalumab. 

Brodalumab will be commercially available around the fall 2017. Before prescribing brodalumab, I will counsel patients about this potential increased risk of suicidal ideation or behavior as noted in the prescribing information, but I will tell them that a true risk has not yet been determined in long-term registries. I will mention to patients that if they really do feel depressed or experience suicidal ideation or behavior after starting brodalumab, they should stop taking brodalumab and contact me or a mental health professional.

—Jashin J. Wu, MD (Los Angeles, California)