Cutis

Altreno Lotion Now Available for Acne Vulgaris

Ortho Dermatologics launches Altreno (tretinoin) Lotion 0.05% for the treatment of acne vulgaris in patients 9 years and older. It was approved by the US Food and Drug Administration in August 2018, providing patients with the efficacy of tretinoin and the tolerability of a lotion formulation containing hyaluronic acid, glycerin, and collagen to help hydrate and moisturize the skin. For more information, visit www.ortho-dermatologics.com.

Bryhali Approved for Plaque Psoriasis in Adults

Ortho Dermatologics announces US Food and Drug Administration approval of Bryhali (halobetasol propionate) Lotion 0.01% for the treatment of plaque psoriasis in adults. Bryhali is a corticosteroid in a novel vehicle lotion with safety established for dosing up to 8 weeks, offering patients a longer duration of use than other topical steroids. For more information, visit www.bryhali.com.

CoolSculpting Cleared for the Submandibular Area

Zeltiq Aesthetics, Inc, an Allergan affiliate, announces US Food and Drug Administration (FDA) clearance of CoolSculpting to treat the submandibular area. The FDA clearance also was expanded to include patients with a body mass index of up to 46.2 when treating the submental and submandibular areas. CoolSculpting is a nonsurgical treatment that works by gently cooling targeted fat cells in the body to induce natural controlled elimination of fat cells without affecting surrounding tissue. CoolSculpting also is cleared for treatment of visible fat bulges on the thighs, abdomen, and flanks. For more information, visit www.coolsculpting.com.

Glytone Age-Defying Vitamin C+E Serum Reduces Signs of Aging

Pierre Fabre Dermo-Cosmetique introduces Glytone Age-Defying Vitamin C+E Serum, a layering serum with time-released, high concentrations of stabilized vitamins C and E combined with red tea flavonoids to deliver antioxidant protection and antiaging benefits. It is indicated for premature aging caused by environmental damage and oxidative stress as well as postprocedure relief. For more information, visit www.glytone-usa.com.

Hyrimoz Biosimilar Approved for Psoriasis

Sandoz, a Novartis Division, announces US Food and Drug Administration (FDA) approval of Hyrimoz (adalimumab-adaz), a biosimilar indicated for the treatment of psoriatic arthritis and plaque psoriasis, as well as rheumatoid arthritis, juvenile idiopathic arthritis in patients 4 years and older, ankylosing spondylitis, adult Crohn disease, and ulcerative colitis. Hyrimoz is the third FDA-approved biosimilar from Sandoz. For more information, visit www.sandoz.com.

Libtayo Approved for SCC

Regeneron Pharmaceuticals, Inc, and sanofi-aventis US LLC, announce US Food and Drug Administration (FDA) approval of Libtayo (cemiplimab-rwlc) for the treatment of patients with metastatic cutaneous squamous cell carcinoma (SCC) or locally advanced cutaneous SCC who are not candidates for curative surgery or radiation. Libtayo is a monoclonal antibody targeting the programmed death receptor 1. Libtayo was evaluated by the FDA under Priority Review and provides physicians with a tool to treat patients with cutaneous SCC who previously had limited options. Libtayo is administered as a 350-mg intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. For more information, visit www.libtayohcp.com.

Restylane Lyft Now Approved for Hand Rejuvenation

Nestlé Skin Health announces US Food and Drug Administration approval of Restylane Lyft with Lidocaine, a hyaluronic acid dermal filler, for the correction of age-related volume loss in the back of the hands for patients older than 21 years. Restylane Lyft with Lidocaine also is indicated for correction of moderate to severe facial wrinkles and folds such as the nasolabial folds, cheek augmentation, and age-related midface contour deficiencies. For more information, visit www.RestylaneUSA.com.

Xepi Launches for Impetigo

Cutanea Life Sciences launches Xepi (ozenoxacin) Cream 1%, a quinolone antimicrobial, for the treatment of impetigo in adult and pediatric patients 2 months or older. Xepi is applied twice daily for 5 days and has been shown to be active against most isolates of Staphylococcus aureus (including methicillin-resistant isolates) and Streptococcus pyogenes, both in vitro and in clinical infections. For more information, visit www.XepiCream.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Altreno Lotion Now Available for Acne Vulgaris

Ortho Dermatologics launches Altreno (tretinoin) Lotion 0.05% for the treatment of acne vulgaris in patients 9 years and older. It was approved by the US Food and Drug Administration in August 2018, providing patients with the efficacy of tretinoin and the tolerability of a lotion formulation containing hyaluronic acid, glycerin, and collagen to help hydrate and moisturize the skin. For more information, visit www.ortho-dermatologics.com.

Bryhali Approved for Plaque Psoriasis in Adults

Ortho Dermatologics announces US Food and Drug Administration approval of Bryhali (halobetasol propionate) Lotion 0.01% for the treatment of plaque psoriasis in adults. Bryhali is a corticosteroid in a novel vehicle lotion with safety established for dosing up to 8 weeks, offering patients a longer duration of use than other topical steroids. For more information, visit www.bryhali.com.

CoolSculpting Cleared for the Submandibular Area

Zeltiq Aesthetics, Inc, an Allergan affiliate, announces US Food and Drug Administration (FDA) clearance of CoolSculpting to treat the submandibular area. The FDA clearance also was expanded to include patients with a body mass index of up to 46.2 when treating the submental and submandibular areas. CoolSculpting is a nonsurgical treatment that works by gently cooling targeted fat cells in the body to induce natural controlled elimination of fat cells without affecting surrounding tissue. CoolSculpting also is cleared for treatment of visible fat bulges on the thighs, abdomen, and flanks. For more information, visit www.coolsculpting.com.

Glytone Age-Defying Vitamin C+E Serum Reduces Signs of Aging

Pierre Fabre Dermo-Cosmetique introduces Glytone Age-Defying Vitamin C+E Serum, a layering serum with time-released, high concentrations of stabilized vitamins C and E combined with red tea flavonoids to deliver antioxidant protection and antiaging benefits. It is indicated for premature aging caused by environmental damage and oxidative stress as well as postprocedure relief. For more information, visit www.glytone-usa.com.

Hyrimoz Biosimilar Approved for Psoriasis

Sandoz, a Novartis Division, announces US Food and Drug Administration (FDA) approval of Hyrimoz (adalimumab-adaz), a biosimilar indicated for the treatment of psoriatic arthritis and plaque psoriasis, as well as rheumatoid arthritis, juvenile idiopathic arthritis in patients 4 years and older, ankylosing spondylitis, adult Crohn disease, and ulcerative colitis. Hyrimoz is the third FDA-approved biosimilar from Sandoz. For more information, visit www.sandoz.com.

Libtayo Approved for SCC

Regeneron Pharmaceuticals, Inc, and sanofi-aventis US LLC, announce US Food and Drug Administration (FDA) approval of Libtayo (cemiplimab-rwlc) for the treatment of patients with metastatic cutaneous squamous cell carcinoma (SCC) or locally advanced cutaneous SCC who are not candidates for curative surgery or radiation. Libtayo is a monoclonal antibody targeting the programmed death receptor 1. Libtayo was evaluated by the FDA under Priority Review and provides physicians with a tool to treat patients with cutaneous SCC who previously had limited options. Libtayo is administered as a 350-mg intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. For more information, visit www.libtayohcp.com.

Restylane Lyft Now Approved for Hand Rejuvenation

Nestlé Skin Health announces US Food and Drug Administration approval of Restylane Lyft with Lidocaine, a hyaluronic acid dermal filler, for the correction of age-related volume loss in the back of the hands for patients older than 21 years. Restylane Lyft with Lidocaine also is indicated for correction of moderate to severe facial wrinkles and folds such as the nasolabial folds, cheek augmentation, and age-related midface contour deficiencies. For more information, visit www.RestylaneUSA.com.

Xepi Launches for Impetigo

Cutanea Life Sciences launches Xepi (ozenoxacin) Cream 1%, a quinolone antimicrobial, for the treatment of impetigo in adult and pediatric patients 2 months or older. Xepi is applied twice daily for 5 days and has been shown to be active against most isolates of Staphylococcus aureus (including methicillin-resistant isolates) and Streptococcus pyogenes, both in vitro and in clinical infections. For more information, visit www.XepiCream.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Altreno Lotion Now Available for Acne Vulgaris

Ortho Dermatologics launches Altreno (tretinoin) Lotion 0.05% for the treatment of acne vulgaris in patients 9 years and older. It was approved by the US Food and Drug Administration in August 2018, providing patients with the efficacy of tretinoin and the tolerability of a lotion formulation containing hyaluronic acid, glycerin, and collagen to help hydrate and moisturize the skin. For more information, visit www.ortho-dermatologics.com.

Bryhali Approved for Plaque Psoriasis in Adults

Ortho Dermatologics announces US Food and Drug Administration approval of Bryhali (halobetasol propionate) Lotion 0.01% for the treatment of plaque psoriasis in adults. Bryhali is a corticosteroid in a novel vehicle lotion with safety established for dosing up to 8 weeks, offering patients a longer duration of use than other topical steroids. For more information, visit www.bryhali.com.

CoolSculpting Cleared for the Submandibular Area

Zeltiq Aesthetics, Inc, an Allergan affiliate, announces US Food and Drug Administration (FDA) clearance of CoolSculpting to treat the submandibular area. The FDA clearance also was expanded to include patients with a body mass index of up to 46.2 when treating the submental and submandibular areas. CoolSculpting is a nonsurgical treatment that works by gently cooling targeted fat cells in the body to induce natural controlled elimination of fat cells without affecting surrounding tissue. CoolSculpting also is cleared for treatment of visible fat bulges on the thighs, abdomen, and flanks. For more information, visit www.coolsculpting.com.

Glytone Age-Defying Vitamin C+E Serum Reduces Signs of Aging

Pierre Fabre Dermo-Cosmetique introduces Glytone Age-Defying Vitamin C+E Serum, a layering serum with time-released, high concentrations of stabilized vitamins C and E combined with red tea flavonoids to deliver antioxidant protection and antiaging benefits. It is indicated for premature aging caused by environmental damage and oxidative stress as well as postprocedure relief. For more information, visit www.glytone-usa.com.

Hyrimoz Biosimilar Approved for Psoriasis

Sandoz, a Novartis Division, announces US Food and Drug Administration (FDA) approval of Hyrimoz (adalimumab-adaz), a biosimilar indicated for the treatment of psoriatic arthritis and plaque psoriasis, as well as rheumatoid arthritis, juvenile idiopathic arthritis in patients 4 years and older, ankylosing spondylitis, adult Crohn disease, and ulcerative colitis. Hyrimoz is the third FDA-approved biosimilar from Sandoz. For more information, visit www.sandoz.com.

Libtayo Approved for SCC

Regeneron Pharmaceuticals, Inc, and sanofi-aventis US LLC, announce US Food and Drug Administration (FDA) approval of Libtayo (cemiplimab-rwlc) for the treatment of patients with metastatic cutaneous squamous cell carcinoma (SCC) or locally advanced cutaneous SCC who are not candidates for curative surgery or radiation. Libtayo is a monoclonal antibody targeting the programmed death receptor 1. Libtayo was evaluated by the FDA under Priority Review and provides physicians with a tool to treat patients with cutaneous SCC who previously had limited options. Libtayo is administered as a 350-mg intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. For more information, visit www.libtayohcp.com.

Restylane Lyft Now Approved for Hand Rejuvenation

Nestlé Skin Health announces US Food and Drug Administration approval of Restylane Lyft with Lidocaine, a hyaluronic acid dermal filler, for the correction of age-related volume loss in the back of the hands for patients older than 21 years. Restylane Lyft with Lidocaine also is indicated for correction of moderate to severe facial wrinkles and folds such as the nasolabial folds, cheek augmentation, and age-related midface contour deficiencies. For more information, visit www.RestylaneUSA.com.

Xepi Launches for Impetigo

Cutanea Life Sciences launches Xepi (ozenoxacin) Cream 1%, a quinolone antimicrobial, for the treatment of impetigo in adult and pediatric patients 2 months or older. Xepi is applied twice daily for 5 days and has been shown to be active against most isolates of Staphylococcus aureus (including methicillin-resistant isolates) and Streptococcus pyogenes, both in vitro and in clinical infections. For more information, visit www.XepiCream.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Cutaneous B-cell lymphomas represent a group of lymphomas derived from B lymphocytes in various stages of differentiation. The skin can be the site of primary or secondary involvement of any of the B-cell lymphomas. Primary cutaneous B-cell lymphomas present in the skin without evidence of extracutaneous disease at the time of diagnosis.¹ The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues recognizes 5 distinct primary cutaneous B-cell lymphoma subtypes: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type; DLBCL, not otherwise specified; and intravascular DLBCL.^1-3 The DLBCL, not otherwise specified, category includes less common provisional entities with insufficient evidence to be recognized as distinct diseases. Epstein-Barr virus (EBV)–positive DLBCL is a rare subtype in this group.⁴

This article reviews the different clinicopathologic subtypes of primary cutaneous B-cell lymphoma. It also serves to help dermatologists recognize primary cutaneous EBV-positive DLBCL as a rare and aggressive form of this disease.

Case Report

An 84-year-old white man presented with a pruritic eruption on the arms, legs, back, neck, and face of 5 months’ duration. His medical history was notable for prostate cancer that was successfully treated with radiation therapy 6 years prior. The patient denied any constitutional symptoms such as fever, chills, night sweats, or weight loss, and review of systems was negative. The patient was taking prednisone, which alleviated the pruritus, but the lesions persisted.

Physical examination revealed multiple pink to erythematous papules and subcutaneous nodules involving the face, neck, back, arms, and legs (Figure 1). No scale, crust, or ulceration was present. Palpation of the cervical, supraclavicular, axillary, and inguinal lymph nodes was negative for lymphadenopathy.

Punch biopsies of representative lesions on the upper back and right arm revealed diffuse and nodular infiltrates of large atypical lymphoid cells with scattered centroblasts and immunoblasts (Figures 2 and 3). Immunohistochemical staining demonstrated CD79, MUM-1, and EBV-encoded RNA positivity among the neoplastic cells. The Ki-67 proliferative index was greater than 90%. The neoplastic cells were negative for CD5, CD10, CD20, CD21, CD30, CD56, CD123, CD138, PAX5, C-MYC, BCL-2, BCL-6, cyclin D1, TCL-1A, and terminal deoxynucleotidyl transferase. Polymerase chain reaction showed a clonal B-cell population.

A peripheral blood smear did not show evidence of a B-cell lymphoproliferative process. A bone marrow biopsy was performed and did not show evidence of B-cell lymphoid neoplasia but did show reactive lymphoid aggregates composed of CD4⁺ and CD10⁺ T cells. Peripheral blood T-cell rearrangement and JAK2 were negative.

Based on clinical and histologic findings, the patient was diagnosed with primary cutaneous EBV-positive DLBCL. The patient was started on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy for treatment of this aggressive cutaneous lymphoma, which initially resulted in clinical improvement of the lesions and complete involution of the subcutaneous nodules. After the sixth cycle of CHOP, he developed faintly erythematous indurated papules on the upper arms, chest, and back. Biopsy confirmed recurrence of the EBV-positive cutaneous lymphoma, and he started salvage chemotherapy with gemcitabine, oxaliplatin, and rituximab every 2 weeks; however, 4 months later (9 months after the initial presentation) he died from complications of the disease.

Comment

Etiology
Epstein-Barr virus–positive DLBCL, also called EBV-positive DLBCL of the elderly, was initially described in 2003 by Oyama et al⁵ and was included as a provisional entity in the 2008 World Health Organization classification system as a rare subtype of the DLBCL, not otherwise specified, category.² It is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in immunocompetent patients older than 50 years.⁶ Epstein-Barr virus is a human herpesvirus that demonstrates tropism for lymphocytes and survives in human hosts by establishing latency in B cells. Under normal immune conditions, the proliferation of EBV-infected B cells is prevented by cytotoxic T cells.⁷ It is important to recognize that patients with EBV-positive DLBCL do not have a known immunodeficiency state; therefore, it has been postulated that EBV-positive DLBCL might be caused by age-related senescence of the immune system.^4,8

Epidemiology and Clinical Features
Epstein-Barr virus–positive DLBCL is more common in Asian countries than in Western countries, and there is a slight male predominance.⁶ A majority of patients present with extranodal disease at the time of diagnosis, and the skin is the most common extranodal site of involvement.^6,9 Rare cases of primary cutaneous involvement also have been described.^7,9,10 Cutaneous manifestations include erythematous papules and subcutaneous nodules. Other sites of extranodal involvement include the lungs, oral cavity, pharynx, gastrointestinal tract, and bone marrow.^8,9 However, EBV-positive DLBCL is an aggressive lymphoma and prognosis is poor irrespective of the primary site of involvement.

Histopathology
Two morphologic subtypes can be seen on histology. The polymorphic pattern is characterized by a broad range of B-cell maturation with admixed reactive cells (eg, lymphocytes, histiocytes, plasma cells). The monomorphic or large-cell pattern is characterized by monotonous sheets of large transformed B cells.^4,11 Many cases show both histologic patterns, and these morphologic variants do not impart any clinical or prognostic significance. Regardless of the histologic subtype, the neoplastic cells express pan B-cell antigens (eg, CD19, CD20, CD79a, PAX5), as well as MUM-1, BCL-2, and EBV-encoded RNA.⁴ Cases with plasmablastic features, as in our patient, may show weak or absent CD20 staining.¹² Detection of EBV by in situ hybridization is required for the diagnosis.

Diagnosis
Workup for a suspected cutaneous lymphoma should include a complete history and physical examination; laboratory studies; and relevant imaging evaluation such as computed tomography of the chest, abdomen, and pelvis with or without whole-body positron emission tomography. A bone marrow biopsy and aspirate also should be performed in all cutaneous lymphomas with intermediate to aggressive clinical behavior. Accurate staging evaluation is integral to confirm the absence of extracutaneous involvement and to provide prognostic and anatomic information for the appropriate selection of treatment.¹³

Prognosis and Management
Primary cutaneous lymphomas tend to have different clinical behaviors and prognoses compared to histologically similar systemic lymphomas; therefore, different therapeutic strategies are warranted.¹⁴ Epstein-Barr virus–positive DLBCL has an aggressive clinical course with a median survival of 2 years.⁸ Patients with EBV-positive DLBCL have a poorer overall survival and treatment response when compared to patients with EBV-negative DLBCLs.⁴ Primary cutaneous B-cell lymphomas with indolent behavior, such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, can be treated with surgical excision, radiation therapy, or observation.¹⁵ No standard treatment exists for EBV-positive DLBCL, but R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is the standard treatment of primary cutaneous DLBCL, leg type, may provide a survival benefit.^13,15 Further studies are required to determine optimal treatment strategies.

Conclusion

Although rare, EBV-positive DLBCL is an important entity to consider when evaluating a patient with a suspected primary cutaneous lymphoma. Workup to rule out an underlying systemic lymphoma with relevant laboratory evaluation, imaging studies, and bone marrow biopsy is critical. Prognosis is poor and treatment is difficult, as standard treatment protocols have yet to be determined.

Cutaneous B-cell lymphomas represent a group of lymphomas derived from B lymphocytes in various stages of differentiation. The skin can be the site of primary or secondary involvement of any of the B-cell lymphomas. Primary cutaneous B-cell lymphomas present in the skin without evidence of extracutaneous disease at the time of diagnosis.¹ The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues recognizes 5 distinct primary cutaneous B-cell lymphoma subtypes: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type; DLBCL, not otherwise specified; and intravascular DLBCL.^1-3 The DLBCL, not otherwise specified, category includes less common provisional entities with insufficient evidence to be recognized as distinct diseases. Epstein-Barr virus (EBV)–positive DLBCL is a rare subtype in this group.⁴

This article reviews the different clinicopathologic subtypes of primary cutaneous B-cell lymphoma. It also serves to help dermatologists recognize primary cutaneous EBV-positive DLBCL as a rare and aggressive form of this disease.

Case Report

An 84-year-old white man presented with a pruritic eruption on the arms, legs, back, neck, and face of 5 months’ duration. His medical history was notable for prostate cancer that was successfully treated with radiation therapy 6 years prior. The patient denied any constitutional symptoms such as fever, chills, night sweats, or weight loss, and review of systems was negative. The patient was taking prednisone, which alleviated the pruritus, but the lesions persisted.

Physical examination revealed multiple pink to erythematous papules and subcutaneous nodules involving the face, neck, back, arms, and legs (Figure 1). No scale, crust, or ulceration was present. Palpation of the cervical, supraclavicular, axillary, and inguinal lymph nodes was negative for lymphadenopathy.

Punch biopsies of representative lesions on the upper back and right arm revealed diffuse and nodular infiltrates of large atypical lymphoid cells with scattered centroblasts and immunoblasts (Figures 2 and 3). Immunohistochemical staining demonstrated CD79, MUM-1, and EBV-encoded RNA positivity among the neoplastic cells. The Ki-67 proliferative index was greater than 90%. The neoplastic cells were negative for CD5, CD10, CD20, CD21, CD30, CD56, CD123, CD138, PAX5, C-MYC, BCL-2, BCL-6, cyclin D1, TCL-1A, and terminal deoxynucleotidyl transferase. Polymerase chain reaction showed a clonal B-cell population.

A peripheral blood smear did not show evidence of a B-cell lymphoproliferative process. A bone marrow biopsy was performed and did not show evidence of B-cell lymphoid neoplasia but did show reactive lymphoid aggregates composed of CD4⁺ and CD10⁺ T cells. Peripheral blood T-cell rearrangement and JAK2 were negative.

Based on clinical and histologic findings, the patient was diagnosed with primary cutaneous EBV-positive DLBCL. The patient was started on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy for treatment of this aggressive cutaneous lymphoma, which initially resulted in clinical improvement of the lesions and complete involution of the subcutaneous nodules. After the sixth cycle of CHOP, he developed faintly erythematous indurated papules on the upper arms, chest, and back. Biopsy confirmed recurrence of the EBV-positive cutaneous lymphoma, and he started salvage chemotherapy with gemcitabine, oxaliplatin, and rituximab every 2 weeks; however, 4 months later (9 months after the initial presentation) he died from complications of the disease.

Comment

Etiology
Epstein-Barr virus–positive DLBCL, also called EBV-positive DLBCL of the elderly, was initially described in 2003 by Oyama et al⁵ and was included as a provisional entity in the 2008 World Health Organization classification system as a rare subtype of the DLBCL, not otherwise specified, category.² It is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in immunocompetent patients older than 50 years.⁶ Epstein-Barr virus is a human herpesvirus that demonstrates tropism for lymphocytes and survives in human hosts by establishing latency in B cells. Under normal immune conditions, the proliferation of EBV-infected B cells is prevented by cytotoxic T cells.⁷ It is important to recognize that patients with EBV-positive DLBCL do not have a known immunodeficiency state; therefore, it has been postulated that EBV-positive DLBCL might be caused by age-related senescence of the immune system.^4,8

Epidemiology and Clinical Features
Epstein-Barr virus–positive DLBCL is more common in Asian countries than in Western countries, and there is a slight male predominance.⁶ A majority of patients present with extranodal disease at the time of diagnosis, and the skin is the most common extranodal site of involvement.^6,9 Rare cases of primary cutaneous involvement also have been described.^7,9,10 Cutaneous manifestations include erythematous papules and subcutaneous nodules. Other sites of extranodal involvement include the lungs, oral cavity, pharynx, gastrointestinal tract, and bone marrow.^8,9 However, EBV-positive DLBCL is an aggressive lymphoma and prognosis is poor irrespective of the primary site of involvement.

Histopathology
Two morphologic subtypes can be seen on histology. The polymorphic pattern is characterized by a broad range of B-cell maturation with admixed reactive cells (eg, lymphocytes, histiocytes, plasma cells). The monomorphic or large-cell pattern is characterized by monotonous sheets of large transformed B cells.^4,11 Many cases show both histologic patterns, and these morphologic variants do not impart any clinical or prognostic significance. Regardless of the histologic subtype, the neoplastic cells express pan B-cell antigens (eg, CD19, CD20, CD79a, PAX5), as well as MUM-1, BCL-2, and EBV-encoded RNA.⁴ Cases with plasmablastic features, as in our patient, may show weak or absent CD20 staining.¹² Detection of EBV by in situ hybridization is required for the diagnosis.

Diagnosis
Workup for a suspected cutaneous lymphoma should include a complete history and physical examination; laboratory studies; and relevant imaging evaluation such as computed tomography of the chest, abdomen, and pelvis with or without whole-body positron emission tomography. A bone marrow biopsy and aspirate also should be performed in all cutaneous lymphomas with intermediate to aggressive clinical behavior. Accurate staging evaluation is integral to confirm the absence of extracutaneous involvement and to provide prognostic and anatomic information for the appropriate selection of treatment.¹³

Prognosis and Management
Primary cutaneous lymphomas tend to have different clinical behaviors and prognoses compared to histologically similar systemic lymphomas; therefore, different therapeutic strategies are warranted.¹⁴ Epstein-Barr virus–positive DLBCL has an aggressive clinical course with a median survival of 2 years.⁸ Patients with EBV-positive DLBCL have a poorer overall survival and treatment response when compared to patients with EBV-negative DLBCLs.⁴ Primary cutaneous B-cell lymphomas with indolent behavior, such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, can be treated with surgical excision, radiation therapy, or observation.¹⁵ No standard treatment exists for EBV-positive DLBCL, but R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is the standard treatment of primary cutaneous DLBCL, leg type, may provide a survival benefit.^13,15 Further studies are required to determine optimal treatment strategies.

Conclusion

Although rare, EBV-positive DLBCL is an important entity to consider when evaluating a patient with a suspected primary cutaneous lymphoma. Workup to rule out an underlying systemic lymphoma with relevant laboratory evaluation, imaging studies, and bone marrow biopsy is critical. Prognosis is poor and treatment is difficult, as standard treatment protocols have yet to be determined.

Cutaneous B-cell lymphomas represent a group of lymphomas derived from B lymphocytes in various stages of differentiation. The skin can be the site of primary or secondary involvement of any of the B-cell lymphomas. Primary cutaneous B-cell lymphomas present in the skin without evidence of extracutaneous disease at the time of diagnosis.¹ The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues recognizes 5 distinct primary cutaneous B-cell lymphoma subtypes: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type; DLBCL, not otherwise specified; and intravascular DLBCL.^1-3 The DLBCL, not otherwise specified, category includes less common provisional entities with insufficient evidence to be recognized as distinct diseases. Epstein-Barr virus (EBV)–positive DLBCL is a rare subtype in this group.⁴

This article reviews the different clinicopathologic subtypes of primary cutaneous B-cell lymphoma. It also serves to help dermatologists recognize primary cutaneous EBV-positive DLBCL as a rare and aggressive form of this disease.

Case Report

An 84-year-old white man presented with a pruritic eruption on the arms, legs, back, neck, and face of 5 months’ duration. His medical history was notable for prostate cancer that was successfully treated with radiation therapy 6 years prior. The patient denied any constitutional symptoms such as fever, chills, night sweats, or weight loss, and review of systems was negative. The patient was taking prednisone, which alleviated the pruritus, but the lesions persisted.

Physical examination revealed multiple pink to erythematous papules and subcutaneous nodules involving the face, neck, back, arms, and legs (Figure 1). No scale, crust, or ulceration was present. Palpation of the cervical, supraclavicular, axillary, and inguinal lymph nodes was negative for lymphadenopathy.

Punch biopsies of representative lesions on the upper back and right arm revealed diffuse and nodular infiltrates of large atypical lymphoid cells with scattered centroblasts and immunoblasts (Figures 2 and 3). Immunohistochemical staining demonstrated CD79, MUM-1, and EBV-encoded RNA positivity among the neoplastic cells. The Ki-67 proliferative index was greater than 90%. The neoplastic cells were negative for CD5, CD10, CD20, CD21, CD30, CD56, CD123, CD138, PAX5, C-MYC, BCL-2, BCL-6, cyclin D1, TCL-1A, and terminal deoxynucleotidyl transferase. Polymerase chain reaction showed a clonal B-cell population.

A peripheral blood smear did not show evidence of a B-cell lymphoproliferative process. A bone marrow biopsy was performed and did not show evidence of B-cell lymphoid neoplasia but did show reactive lymphoid aggregates composed of CD4⁺ and CD10⁺ T cells. Peripheral blood T-cell rearrangement and JAK2 were negative.

Based on clinical and histologic findings, the patient was diagnosed with primary cutaneous EBV-positive DLBCL. The patient was started on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy for treatment of this aggressive cutaneous lymphoma, which initially resulted in clinical improvement of the lesions and complete involution of the subcutaneous nodules. After the sixth cycle of CHOP, he developed faintly erythematous indurated papules on the upper arms, chest, and back. Biopsy confirmed recurrence of the EBV-positive cutaneous lymphoma, and he started salvage chemotherapy with gemcitabine, oxaliplatin, and rituximab every 2 weeks; however, 4 months later (9 months after the initial presentation) he died from complications of the disease.

Comment

Etiology
Epstein-Barr virus–positive DLBCL, also called EBV-positive DLBCL of the elderly, was initially described in 2003 by Oyama et al⁵ and was included as a provisional entity in the 2008 World Health Organization classification system as a rare subtype of the DLBCL, not otherwise specified, category.² It is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in immunocompetent patients older than 50 years.⁶ Epstein-Barr virus is a human herpesvirus that demonstrates tropism for lymphocytes and survives in human hosts by establishing latency in B cells. Under normal immune conditions, the proliferation of EBV-infected B cells is prevented by cytotoxic T cells.⁷ It is important to recognize that patients with EBV-positive DLBCL do not have a known immunodeficiency state; therefore, it has been postulated that EBV-positive DLBCL might be caused by age-related senescence of the immune system.^4,8

Epidemiology and Clinical Features
Epstein-Barr virus–positive DLBCL is more common in Asian countries than in Western countries, and there is a slight male predominance.⁶ A majority of patients present with extranodal disease at the time of diagnosis, and the skin is the most common extranodal site of involvement.^6,9 Rare cases of primary cutaneous involvement also have been described.^7,9,10 Cutaneous manifestations include erythematous papules and subcutaneous nodules. Other sites of extranodal involvement include the lungs, oral cavity, pharynx, gastrointestinal tract, and bone marrow.^8,9 However, EBV-positive DLBCL is an aggressive lymphoma and prognosis is poor irrespective of the primary site of involvement.

Histopathology
Two morphologic subtypes can be seen on histology. The polymorphic pattern is characterized by a broad range of B-cell maturation with admixed reactive cells (eg, lymphocytes, histiocytes, plasma cells). The monomorphic or large-cell pattern is characterized by monotonous sheets of large transformed B cells.^4,11 Many cases show both histologic patterns, and these morphologic variants do not impart any clinical or prognostic significance. Regardless of the histologic subtype, the neoplastic cells express pan B-cell antigens (eg, CD19, CD20, CD79a, PAX5), as well as MUM-1, BCL-2, and EBV-encoded RNA.⁴ Cases with plasmablastic features, as in our patient, may show weak or absent CD20 staining.¹² Detection of EBV by in situ hybridization is required for the diagnosis.

Diagnosis
Workup for a suspected cutaneous lymphoma should include a complete history and physical examination; laboratory studies; and relevant imaging evaluation such as computed tomography of the chest, abdomen, and pelvis with or without whole-body positron emission tomography. A bone marrow biopsy and aspirate also should be performed in all cutaneous lymphomas with intermediate to aggressive clinical behavior. Accurate staging evaluation is integral to confirm the absence of extracutaneous involvement and to provide prognostic and anatomic information for the appropriate selection of treatment.¹³

Prognosis and Management
Primary cutaneous lymphomas tend to have different clinical behaviors and prognoses compared to histologically similar systemic lymphomas; therefore, different therapeutic strategies are warranted.¹⁴ Epstein-Barr virus–positive DLBCL has an aggressive clinical course with a median survival of 2 years.⁸ Patients with EBV-positive DLBCL have a poorer overall survival and treatment response when compared to patients with EBV-negative DLBCLs.⁴ Primary cutaneous B-cell lymphomas with indolent behavior, such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, can be treated with surgical excision, radiation therapy, or observation.¹⁵ No standard treatment exists for EBV-positive DLBCL, but R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is the standard treatment of primary cutaneous DLBCL, leg type, may provide a survival benefit.^13,15 Further studies are required to determine optimal treatment strategies.

Conclusion

Although rare, EBV-positive DLBCL is an important entity to consider when evaluating a patient with a suspected primary cutaneous lymphoma. Workup to rule out an underlying systemic lymphoma with relevant laboratory evaluation, imaging studies, and bone marrow biopsy is critical. Prognosis is poor and treatment is difficult, as standard treatment protocols have yet to be determined.

Numerous highly efficacious treatment modalities exist in dermatology, yet patients may be highly wary of their possible adverse events, even when those risks are rare.^1,2 Such fears can lead to poor medication adherence and treatment refusal. A key determinant in successful patient-provider care is to effectively communicate risk. The communication of risk is hampered by the lack of any common currency for comparing risks. The development of a standardized unit of risk could help facilitate risk comparisons, allowing physicians and patients to put risk levels into better perspective.

One easily relatable event is the risk of injury in an automobile crash. Driving, whether to the dermatology clinic for a monitoring visit or to the supermarket for weekly groceries, is associated with risk of injury and death. The risk of automobile-related injury warranting a visit to the emergency department could provide a comparator that physicians can use to give patients a more objective sense of treatment risks or to introduce the justification of a monitoring visit. The objective of this study was to develop a standard risk unit based on the lifetime risk (LTR) of automobile injury and to compare this unit of risk to various risks of dermatologic treatments.

Methods

Literature Review
We first identified common risks in dermatology that would be illustrative and then identified keywords. PubMed searches for articles indexed for MEDLINE from November 1996 to February 2017 were performed combining the following terms: (relative risk, odds ratio, lifetime risk) and (isotretinoin, IBD; melanoma, SCC, transplantation; indoor tanning, BCC, SCC; transplant and SCC; biologics and tuberculosis; hydroxychloroquine retinal toxicity; psoriasis and psoriatic arthritis). An additional search was performed in June 2018 including the term blindness and injectable fillers. Our search combined these terms in numerous ways. Results were focused on meta-analyses and observational studies.

The references of relevant studies were included. Articles not focused on meta-analyses but rather on observational studies were individually analyzed for quality and bias using the 9-point Newcastle-Ottawa Scale, with a score of 7 or more as a cutoff for inclusion.

Determination of Risk Comparators
Data from the 2016 National Safety Council’s Injury Facts report were searched for nonmedical-related risk comparators, such as the risk of death by dog attack, by lightning, and by fire or smoke.³ Data from the 2015 US Department of Transportation Traffic Safety Facts were searched for relatable risk comparators, such as the LTR of automobile death and injury.⁴

Definitions
Automobile injury was defined as an injury warranting a visit to the emergency department.⁵ Automobile was defined as a road vehicle with 4 wheels and powered by an internal combustion engine or electric motor.⁶ This definition excluded light trucks, large trucks, and motorcycles.

LTR Calculation
Lifetime risk was used as the comparative measure. Lifetime risk is a type of absolute risk that depicts the probability that a specific disease or event will occur in an individual’s lifespan. The LTRof developing a disease or adverse event due to a dermatologic therapy or interventionwas denoted as LTR_{adverse event} and calculated by the following equation^7,8:

In this equation, LTR_{general population} is the LTR of developing the disease or adverse event without being subject to the therapy or intervention, and RR_intervention is the relative risk (RR) from previously published RR data (relating to the development of the disease in question or an adverse event of the intervention). The use of equation (1) holds true only when the absolute risk of developing the disease or adverse event (LTR_{general population}) is low.⁷ Although the calculation of an LTR using a constant lifetime RR may require major approximations, studies evaluating the variation of RR over time are sparse.^7,9 The Newcastle-Ottawa Scale was used to control such variance; only high-quality, nonrandomized studies were included. Although the use of residual LTR would be preferable, as LTR depends on age, such epidemiological data do not exist for complex diseases.

When not available, the LTR_{general population} was calculated from the rate of disease (cases per 100,000 individuals per year) multiplied by the average lifespan of an American (78.8 years)¹⁰:

When an odds ratio (OR) was presented, its conversion to RR followed¹¹:

In this equation, R_C is the absolute risk in the unexposed group. If the prevalence of the disease was considered low, the rare disease assumption was implemented as the following^11,12:

The use of this approximation overestimates the LTR of an event. From a patient perspective, this approach is conservative. If prior LTR values were available, such as the LTR of automobile injury, automobile death, or other intervention, they were used without the need for calculation.

Unit Comparator
The LTRs of all adverse events were normalized to a unit comparator, using the LTR of an automobile injury as reference point, denoted as 1 risk unit (RU):

This equation allows for quick comparison of the magnitude of LTRs between events. Events with an RU less than 1 are less likely to occur than the risk of automobile injury; events with an RU greater than 1 are more likely than the risk of automobile injury. All RR, LTR, and unit comparators were presented as a single pooled estimate of their respective upper-limit CIs. The use of the upper-limit CI conservatively overestimates the LTR of an event.

Results

Ten dermatologic interventions were identified as illustrative, to be presented alongside the risk of automobile injury and death. The LTR of automobile injury was 32%, defined as 1.0 RU. The LTR of automobile death was 0.89% (1/36 RU).

Two events had LTRs roughly similar to automobile injury: development of a subsequent basal cell carcinoma within 3 years (1.4 RU) and development of a squamous cell carcinoma (SCC) secondary to indoor tanning (1.6 RU). Development of SCC following organ transplantation (34 RU) was considerably more likely than automobile injury. All other identified events had lower RUs than automobile injury (Table). Three events with small RUs included tuberculosis development with a tumor necrosis factor α inhibitor (1/32 RU), Crohn disease development with isotretinoin (1/41 RU), and blindness following facial hyaluronic acid injection (1/80 RU). The LTR of death by dog attack (1/42,436 RU) and death by lightning strike (1/36,542 RU) also had small RUs.

The unit comparators from the Table were adapted into graphic form to depict risk relative to the risk of automobile injury (Figure).

Comment

Numerous interventions in dermatology offer much less risk of an adverse event than the LTR of automobile injury. However, this concept of risk includes only the likelihood of development of an event, not the severity of the measured event, as our numerical and visual tool objectively captures the related risks using an RU comparator. Such use of a standardized RU demonstrates the essence of risk; “zero risk” does not exist, and each intervention or treatment, albeit how small, must be justified in concordance with other types of risk, such as the automobile.

The development of adverse events secondary to dermatologic intervention or therapy, for which monitoring visits are utilized, were used as important comparators to the risk of automobile injury. The continuous practice of monitoring visits may increase patient’s fears regarding possible adverse events secondary to therapy. Hydroxychloroquine retinal toxicity (1/16 RU) and psoriatic arthritis development following severe psoriasis (1/3.9 RU) were less likely to occur than automobile injury. The development of abnormal blood counts or blood tests secondary to therapy or intervention could not be formatted into an RU. The use of equation (1) for the calculation of LTR_{adverse event}holds true only when the absolute risk of developing the adverse event in the general population—in this case, abnormal blood counts or blood tests—is low.⁷

Although the unit comparator allows for the comparison of different dermatologic risk, a limitation of the RU model and its visual tool are a dependence on RR, a value that changes following publication of new studies. A solution was the use of a single pooled estimate to represent the upper-limit CIs of LTR. This practice overestimates risk. As with RR, new automobile injury rates are published annually.¹⁰ In the last 5 years, the LTR of automobile injury has stayed relatively constant: between 32% and 33%.⁴ Although the RU calculations and Figure included a wide variety of interventions in dermatology, select clinical situations were not included. It is beyond the scope of this article to systematically review all risk in dermatology but rather introduce the concept of the RU founded on automobile-associated risks. With the introduction of a methodical framework, the reader is invited to calculate RUs pertinent to their clinical interests.

Any intervention or treatment in dermatology is accompanied by risk. The use of a unit comparator using an easily relatable event—the LTR of automobile injury—allows the patient to easily compare risk and internally justify the practice of monitoring visits. Inclusion of a visual tool, such as the Figure, might alleviate many irrational fears that accompany some of the highly effective treatments and interventions used in dermatology and thus lead to better patient outcomes.

Acknowledgment
We thank Taranjeet Singh, MS (Dunn, North Carolina), for her comments on an earlier version of the manuscript.

Numerous highly efficacious treatment modalities exist in dermatology, yet patients may be highly wary of their possible adverse events, even when those risks are rare.^1,2 Such fears can lead to poor medication adherence and treatment refusal. A key determinant in successful patient-provider care is to effectively communicate risk. The communication of risk is hampered by the lack of any common currency for comparing risks. The development of a standardized unit of risk could help facilitate risk comparisons, allowing physicians and patients to put risk levels into better perspective.

One easily relatable event is the risk of injury in an automobile crash. Driving, whether to the dermatology clinic for a monitoring visit or to the supermarket for weekly groceries, is associated with risk of injury and death. The risk of automobile-related injury warranting a visit to the emergency department could provide a comparator that physicians can use to give patients a more objective sense of treatment risks or to introduce the justification of a monitoring visit. The objective of this study was to develop a standard risk unit based on the lifetime risk (LTR) of automobile injury and to compare this unit of risk to various risks of dermatologic treatments.

Methods

Literature Review
We first identified common risks in dermatology that would be illustrative and then identified keywords. PubMed searches for articles indexed for MEDLINE from November 1996 to February 2017 were performed combining the following terms: (relative risk, odds ratio, lifetime risk) and (isotretinoin, IBD; melanoma, SCC, transplantation; indoor tanning, BCC, SCC; transplant and SCC; biologics and tuberculosis; hydroxychloroquine retinal toxicity; psoriasis and psoriatic arthritis). An additional search was performed in June 2018 including the term blindness and injectable fillers. Our search combined these terms in numerous ways. Results were focused on meta-analyses and observational studies.

The references of relevant studies were included. Articles not focused on meta-analyses but rather on observational studies were individually analyzed for quality and bias using the 9-point Newcastle-Ottawa Scale, with a score of 7 or more as a cutoff for inclusion.

Determination of Risk Comparators
Data from the 2016 National Safety Council’s Injury Facts report were searched for nonmedical-related risk comparators, such as the risk of death by dog attack, by lightning, and by fire or smoke.³ Data from the 2015 US Department of Transportation Traffic Safety Facts were searched for relatable risk comparators, such as the LTR of automobile death and injury.⁴

Definitions
Automobile injury was defined as an injury warranting a visit to the emergency department.⁵ Automobile was defined as a road vehicle with 4 wheels and powered by an internal combustion engine or electric motor.⁶ This definition excluded light trucks, large trucks, and motorcycles.

LTR Calculation
Lifetime risk was used as the comparative measure. Lifetime risk is a type of absolute risk that depicts the probability that a specific disease or event will occur in an individual’s lifespan. The LTRof developing a disease or adverse event due to a dermatologic therapy or interventionwas denoted as LTR_{adverse event} and calculated by the following equation^7,8:

In this equation, LTR_{general population} is the LTR of developing the disease or adverse event without being subject to the therapy or intervention, and RR_intervention is the relative risk (RR) from previously published RR data (relating to the development of the disease in question or an adverse event of the intervention). The use of equation (1) holds true only when the absolute risk of developing the disease or adverse event (LTR_{general population}) is low.⁷ Although the calculation of an LTR using a constant lifetime RR may require major approximations, studies evaluating the variation of RR over time are sparse.^7,9 The Newcastle-Ottawa Scale was used to control such variance; only high-quality, nonrandomized studies were included. Although the use of residual LTR would be preferable, as LTR depends on age, such epidemiological data do not exist for complex diseases.

When not available, the LTR_{general population} was calculated from the rate of disease (cases per 100,000 individuals per year) multiplied by the average lifespan of an American (78.8 years)¹⁰:

When an odds ratio (OR) was presented, its conversion to RR followed¹¹:

In this equation, R_C is the absolute risk in the unexposed group. If the prevalence of the disease was considered low, the rare disease assumption was implemented as the following^11,12:

The use of this approximation overestimates the LTR of an event. From a patient perspective, this approach is conservative. If prior LTR values were available, such as the LTR of automobile injury, automobile death, or other intervention, they were used without the need for calculation.

Unit Comparator
The LTRs of all adverse events were normalized to a unit comparator, using the LTR of an automobile injury as reference point, denoted as 1 risk unit (RU):

This equation allows for quick comparison of the magnitude of LTRs between events. Events with an RU less than 1 are less likely to occur than the risk of automobile injury; events with an RU greater than 1 are more likely than the risk of automobile injury. All RR, LTR, and unit comparators were presented as a single pooled estimate of their respective upper-limit CIs. The use of the upper-limit CI conservatively overestimates the LTR of an event.

Results

Ten dermatologic interventions were identified as illustrative, to be presented alongside the risk of automobile injury and death. The LTR of automobile injury was 32%, defined as 1.0 RU. The LTR of automobile death was 0.89% (1/36 RU).

Two events had LTRs roughly similar to automobile injury: development of a subsequent basal cell carcinoma within 3 years (1.4 RU) and development of a squamous cell carcinoma (SCC) secondary to indoor tanning (1.6 RU). Development of SCC following organ transplantation (34 RU) was considerably more likely than automobile injury. All other identified events had lower RUs than automobile injury (Table). Three events with small RUs included tuberculosis development with a tumor necrosis factor α inhibitor (1/32 RU), Crohn disease development with isotretinoin (1/41 RU), and blindness following facial hyaluronic acid injection (1/80 RU). The LTR of death by dog attack (1/42,436 RU) and death by lightning strike (1/36,542 RU) also had small RUs.

The unit comparators from the Table were adapted into graphic form to depict risk relative to the risk of automobile injury (Figure).

Comment

Numerous interventions in dermatology offer much less risk of an adverse event than the LTR of automobile injury. However, this concept of risk includes only the likelihood of development of an event, not the severity of the measured event, as our numerical and visual tool objectively captures the related risks using an RU comparator. Such use of a standardized RU demonstrates the essence of risk; “zero risk” does not exist, and each intervention or treatment, albeit how small, must be justified in concordance with other types of risk, such as the automobile.

The development of adverse events secondary to dermatologic intervention or therapy, for which monitoring visits are utilized, were used as important comparators to the risk of automobile injury. The continuous practice of monitoring visits may increase patient’s fears regarding possible adverse events secondary to therapy. Hydroxychloroquine retinal toxicity (1/16 RU) and psoriatic arthritis development following severe psoriasis (1/3.9 RU) were less likely to occur than automobile injury. The development of abnormal blood counts or blood tests secondary to therapy or intervention could not be formatted into an RU. The use of equation (1) for the calculation of LTR_{adverse event}holds true only when the absolute risk of developing the adverse event in the general population—in this case, abnormal blood counts or blood tests—is low.⁷

Although the unit comparator allows for the comparison of different dermatologic risk, a limitation of the RU model and its visual tool are a dependence on RR, a value that changes following publication of new studies. A solution was the use of a single pooled estimate to represent the upper-limit CIs of LTR. This practice overestimates risk. As with RR, new automobile injury rates are published annually.¹⁰ In the last 5 years, the LTR of automobile injury has stayed relatively constant: between 32% and 33%.⁴ Although the RU calculations and Figure included a wide variety of interventions in dermatology, select clinical situations were not included. It is beyond the scope of this article to systematically review all risk in dermatology but rather introduce the concept of the RU founded on automobile-associated risks. With the introduction of a methodical framework, the reader is invited to calculate RUs pertinent to their clinical interests.

Any intervention or treatment in dermatology is accompanied by risk. The use of a unit comparator using an easily relatable event—the LTR of automobile injury—allows the patient to easily compare risk and internally justify the practice of monitoring visits. Inclusion of a visual tool, such as the Figure, might alleviate many irrational fears that accompany some of the highly effective treatments and interventions used in dermatology and thus lead to better patient outcomes.

Acknowledgment
We thank Taranjeet Singh, MS (Dunn, North Carolina), for her comments on an earlier version of the manuscript.

Numerous highly efficacious treatment modalities exist in dermatology, yet patients may be highly wary of their possible adverse events, even when those risks are rare.^1,2 Such fears can lead to poor medication adherence and treatment refusal. A key determinant in successful patient-provider care is to effectively communicate risk. The communication of risk is hampered by the lack of any common currency for comparing risks. The development of a standardized unit of risk could help facilitate risk comparisons, allowing physicians and patients to put risk levels into better perspective.

One easily relatable event is the risk of injury in an automobile crash. Driving, whether to the dermatology clinic for a monitoring visit or to the supermarket for weekly groceries, is associated with risk of injury and death. The risk of automobile-related injury warranting a visit to the emergency department could provide a comparator that physicians can use to give patients a more objective sense of treatment risks or to introduce the justification of a monitoring visit. The objective of this study was to develop a standard risk unit based on the lifetime risk (LTR) of automobile injury and to compare this unit of risk to various risks of dermatologic treatments.

Methods

Literature Review
We first identified common risks in dermatology that would be illustrative and then identified keywords. PubMed searches for articles indexed for MEDLINE from November 1996 to February 2017 were performed combining the following terms: (relative risk, odds ratio, lifetime risk) and (isotretinoin, IBD; melanoma, SCC, transplantation; indoor tanning, BCC, SCC; transplant and SCC; biologics and tuberculosis; hydroxychloroquine retinal toxicity; psoriasis and psoriatic arthritis). An additional search was performed in June 2018 including the term blindness and injectable fillers. Our search combined these terms in numerous ways. Results were focused on meta-analyses and observational studies.

The references of relevant studies were included. Articles not focused on meta-analyses but rather on observational studies were individually analyzed for quality and bias using the 9-point Newcastle-Ottawa Scale, with a score of 7 or more as a cutoff for inclusion.

Determination of Risk Comparators
Data from the 2016 National Safety Council’s Injury Facts report were searched for nonmedical-related risk comparators, such as the risk of death by dog attack, by lightning, and by fire or smoke.³ Data from the 2015 US Department of Transportation Traffic Safety Facts were searched for relatable risk comparators, such as the LTR of automobile death and injury.⁴

Definitions
Automobile injury was defined as an injury warranting a visit to the emergency department.⁵ Automobile was defined as a road vehicle with 4 wheels and powered by an internal combustion engine or electric motor.⁶ This definition excluded light trucks, large trucks, and motorcycles.

LTR Calculation
Lifetime risk was used as the comparative measure. Lifetime risk is a type of absolute risk that depicts the probability that a specific disease or event will occur in an individual’s lifespan. The LTRof developing a disease or adverse event due to a dermatologic therapy or interventionwas denoted as LTR_{adverse event} and calculated by the following equation^7,8:

In this equation, LTR_{general population} is the LTR of developing the disease or adverse event without being subject to the therapy or intervention, and RR_intervention is the relative risk (RR) from previously published RR data (relating to the development of the disease in question or an adverse event of the intervention). The use of equation (1) holds true only when the absolute risk of developing the disease or adverse event (LTR_{general population}) is low.⁷ Although the calculation of an LTR using a constant lifetime RR may require major approximations, studies evaluating the variation of RR over time are sparse.^7,9 The Newcastle-Ottawa Scale was used to control such variance; only high-quality, nonrandomized studies were included. Although the use of residual LTR would be preferable, as LTR depends on age, such epidemiological data do not exist for complex diseases.

When not available, the LTR_{general population} was calculated from the rate of disease (cases per 100,000 individuals per year) multiplied by the average lifespan of an American (78.8 years)¹⁰:

When an odds ratio (OR) was presented, its conversion to RR followed¹¹:

In this equation, R_C is the absolute risk in the unexposed group. If the prevalence of the disease was considered low, the rare disease assumption was implemented as the following^11,12:

The use of this approximation overestimates the LTR of an event. From a patient perspective, this approach is conservative. If prior LTR values were available, such as the LTR of automobile injury, automobile death, or other intervention, they were used without the need for calculation.

Unit Comparator
The LTRs of all adverse events were normalized to a unit comparator, using the LTR of an automobile injury as reference point, denoted as 1 risk unit (RU):

This equation allows for quick comparison of the magnitude of LTRs between events. Events with an RU less than 1 are less likely to occur than the risk of automobile injury; events with an RU greater than 1 are more likely than the risk of automobile injury. All RR, LTR, and unit comparators were presented as a single pooled estimate of their respective upper-limit CIs. The use of the upper-limit CI conservatively overestimates the LTR of an event.

Results

Ten dermatologic interventions were identified as illustrative, to be presented alongside the risk of automobile injury and death. The LTR of automobile injury was 32%, defined as 1.0 RU. The LTR of automobile death was 0.89% (1/36 RU).

Two events had LTRs roughly similar to automobile injury: development of a subsequent basal cell carcinoma within 3 years (1.4 RU) and development of a squamous cell carcinoma (SCC) secondary to indoor tanning (1.6 RU). Development of SCC following organ transplantation (34 RU) was considerably more likely than automobile injury. All other identified events had lower RUs than automobile injury (Table). Three events with small RUs included tuberculosis development with a tumor necrosis factor α inhibitor (1/32 RU), Crohn disease development with isotretinoin (1/41 RU), and blindness following facial hyaluronic acid injection (1/80 RU). The LTR of death by dog attack (1/42,436 RU) and death by lightning strike (1/36,542 RU) also had small RUs.

The unit comparators from the Table were adapted into graphic form to depict risk relative to the risk of automobile injury (Figure).

Comment

Numerous interventions in dermatology offer much less risk of an adverse event than the LTR of automobile injury. However, this concept of risk includes only the likelihood of development of an event, not the severity of the measured event, as our numerical and visual tool objectively captures the related risks using an RU comparator. Such use of a standardized RU demonstrates the essence of risk; “zero risk” does not exist, and each intervention or treatment, albeit how small, must be justified in concordance with other types of risk, such as the automobile.

The development of adverse events secondary to dermatologic intervention or therapy, for which monitoring visits are utilized, were used as important comparators to the risk of automobile injury. The continuous practice of monitoring visits may increase patient’s fears regarding possible adverse events secondary to therapy. Hydroxychloroquine retinal toxicity (1/16 RU) and psoriatic arthritis development following severe psoriasis (1/3.9 RU) were less likely to occur than automobile injury. The development of abnormal blood counts or blood tests secondary to therapy or intervention could not be formatted into an RU. The use of equation (1) for the calculation of LTR_{adverse event}holds true only when the absolute risk of developing the adverse event in the general population—in this case, abnormal blood counts or blood tests—is low.⁷

Although the unit comparator allows for the comparison of different dermatologic risk, a limitation of the RU model and its visual tool are a dependence on RR, a value that changes following publication of new studies. A solution was the use of a single pooled estimate to represent the upper-limit CIs of LTR. This practice overestimates risk. As with RR, new automobile injury rates are published annually.¹⁰ In the last 5 years, the LTR of automobile injury has stayed relatively constant: between 32% and 33%.⁴ Although the RU calculations and Figure included a wide variety of interventions in dermatology, select clinical situations were not included. It is beyond the scope of this article to systematically review all risk in dermatology but rather introduce the concept of the RU founded on automobile-associated risks. With the introduction of a methodical framework, the reader is invited to calculate RUs pertinent to their clinical interests.

Any intervention or treatment in dermatology is accompanied by risk. The use of a unit comparator using an easily relatable event—the LTR of automobile injury—allows the patient to easily compare risk and internally justify the practice of monitoring visits. Inclusion of a visual tool, such as the Figure, might alleviate many irrational fears that accompany some of the highly effective treatments and interventions used in dermatology and thus lead to better patient outcomes.

Acknowledgment
We thank Taranjeet Singh, MS (Dunn, North Carolina), for her comments on an earlier version of the manuscript.

Sarcoidosis is a multiorgan, systemic, granulomatous disease that most commonly affects the cutaneous, pulmonary, ocular, and cardiac organ systems. Cutaneous involvement occurs in approximately 20% to 35% of patients, with approximately 25% of patients demonstrating only dermatologic findings.¹ Cutaneous sarcoidosis can have a highly variable presentation. Ichthyosiform sarcoidosis (IS) is a rare form of this disease that has been described as presenting as polygonal adherent scales.² It often is associated with internal organ involvement. We present a case of IS without any organ system involvement at the time of diagnosis. A review of the English-language literature was performed to ascertain the internal organ associations most commonly reported with IS.

Case Report

A 66-year-old black woman presented to dermatology with dark scaly patches noted by her primary care physician to be present on both of the lower extremities. The patient believed they were present for at least 4 years. She described dark spots confined to the lower legs that had gradually increased in size. Review of systems was negative for fever, chills, night sweats, weight loss, vision changes, cough, dyspnea, and joint pains, and there was no history of either personal or familial cutaneous diseases.

Physical examination revealed cutaneous patches of thin white scale with a sharp edge in arciform patterns on the lower extremities. Several of these patches were hyperpigmented and xerotic in appearance (Figure 1). The patches were limited to the lower legs, with no other lesions noted.

A punch biopsy of the skin on the right lower leg was performed. Histopathologic analysis showed epidermal compact hyperkeratosis with deep granulomatous infiltration into the subcutaneous tissue (Figures 2A and 2B). At high power, these granulomas were noted to be noncaseating naked granulomas composed of epithelioid histiocytes surrounded by sparse lymphocytic inflammation (Figure 2C). Special stains including acid-fast bacilli, Fite, and periodic acid–Schiff were negative. The diagnosis of IS was made based on clinical presentation and primarily by histopathologic analysis.

The patient’s cutaneous lesions were treated with fluocinonide ointment 0.05% twice daily. Although she did not notice a dramatic improvement in the plaques, they stabilized in size. Her primary care physician was notified and advised to begin a workup for involvement of other organ systems by sarcoidosis. Her initial evaluation, which included a chest radiograph and electrocardiogram, were unremarkable. Despite multiple attempts to persuade the patient to return for further follow-up, neither dermatology nor her primary care physician were able to complete a full workup.

Comment

Etiology
Although there are several theories regarding the etiology of sarcoidosis, the exact cause remains unknown. The body’s immune response, infectious agents, genetics, and the environment have all been thought to play a role. It has been well established that helper T cell (T_H1) production of interferon and increased levels of tumor necrosis factor propagate the inflammatory response seen in sarcoidosis.³ More recently, T_H17 cells have been found in cutaneous lesions, bronchoalveolar lavage samples, and the blood of patients with sarcoidosis, especially in those with active disease progression.³ Infectious agents such as mycobacteria and propionibacteria DNA or RNA also have been found in sarcoid samples.⁴ Several HLA-DRB1 variants have been associated with an increased incidence of sarcoidosis.⁵

Presentation
Characteristic dermatologic findings of sarcoidosis include macules, papules, nodules, and plaques located on the face, especially the nose, cheeks, and ears, and on the shins or ankles, as well as similar lesions around tattoos or scars. Sarcoid lesions also have been described as angiolupoid, lichenoid, annular, verrucous, ulcerative, and psoriasiform. Here we present an example of the uncommon type, ichthyosiform. Ichthyosiform sarcoidosis is a rare variant described primarily in dark-skinned individuals, a finding supported by both our case and prior reports. Most reported cases have described IS lesions as having a pasted-on appearance, with adherent centers on the extensor surfaces of the lower extremities, head, and/or neck.⁶ Our case follows this descriptive pattern previously reported with adherent patches limited to the lower extremities.

Histopathology
The key histopathologic finding is the presence of noncaseating granulomas on biopsy. Sarcoid “specific” lesions rest on the identification of the noncaseating granulomas, while “nonspecific” lesions such as erythema nodosum fail to demonstrate this finding.¹

Systemic Involvement
The IS type is believed to be an excellent marker for systemic disease, with approximately 95% of reported cases having some form of systemic illness.⁶ Acquired ichthyosis should warrant further investigation for systemic disease. Early recognition could be beneficial for the patient because the ichthyosiform type is believed to precede the diagnosis of systemic disease in most cases by a median of 3 months.⁶

The most common site of internal sarcoid involvement is the lungs, but the lymph nodes, eyes, liver, spleen, heart, and central nervous system also can be involved. Patients can present with nonspecific symptoms such as erythema nodosum in the skin, dyspnea, cough, chest pain, vision changes, enlarged lymph nodes, headaches, joint pain, fever, fatigue, weight loss, and malaise. According to a PubMed search of articles indexed for MEDLINE using the term ichthyosiform sarcoidosis, 16 cases have been reported in the English-language literature (eTable).^1,6-14 Of these 16 cases, 3 involved men and 13 involved women. The median age of a patient diagnosed with IS was 37 years. The respiratory system was found to be the most common organ system involved (14 of 16 patients), with hilar adenopathy and restrictive lung disease being the most common findings. Neurologic findings and hepatic involvement also were seen in 3 and 3 patients, respectively. Eight of 16 cases had an elevated serum angiotensin-converting enzyme level. Details of systemic involvement in other cases of IS are listed in the eTable.

Management
Most patients are given topical corticosteroids for their cutaneous lesions, but patients with systemic involvement will likely need some type of systemic immunosuppressive therapy to control their disease. Systemic therapy often is warranted in IS because of reports of rapid progression. Our case differs from these prior reports in the relative stability of the disease at the last patient encounter. Systemic treatment commonly includes oral corticosteroids such as prednisone. Other options, such as hydroxychloroquine, methotrexate, azathioprine, pentoxifylline, thalidomide, cyclophosphamide, cyclosporine, and infliximab, can be considered if other treatments fail.¹³ Ichthyosiform sarcoidosis patients should continue to have regular follow-up to monitor for disease progression.

Differential
When evaluating an acquired ichthyosis, dermatologists can consider other associations such as Hodgkin disease, hypothyroidism, multiple myeloma, carcinomatosis, and chronic malnutrition.¹ Skin biopsy demonstrating granuloma formation also is not specific for sarcoidosis. Other etiologies, such as autoimmune diseases, immunodeficiency disorders, infections, foreign body granulomas, neoplasms, and drug reactions, should be considered.¹⁵ All patients with acquired ichthyosis should undergo a thorough evaluation for internal involvement.

Conclusion

We presented a case of IS, a rare type of sarcoidosis commonly associated with further internal involvement of the respiratory, nervous, or hepatic organ systems. Recognition of an acquired form of ichthyosis and its potential disease associations, including sarcoidosis, is important to improve early detection of any internal disease, allowing prompt initiation of treatment.

Sarcoidosis is a multiorgan, systemic, granulomatous disease that most commonly affects the cutaneous, pulmonary, ocular, and cardiac organ systems. Cutaneous involvement occurs in approximately 20% to 35% of patients, with approximately 25% of patients demonstrating only dermatologic findings.¹ Cutaneous sarcoidosis can have a highly variable presentation. Ichthyosiform sarcoidosis (IS) is a rare form of this disease that has been described as presenting as polygonal adherent scales.² It often is associated with internal organ involvement. We present a case of IS without any organ system involvement at the time of diagnosis. A review of the English-language literature was performed to ascertain the internal organ associations most commonly reported with IS.

Case Report

A 66-year-old black woman presented to dermatology with dark scaly patches noted by her primary care physician to be present on both of the lower extremities. The patient believed they were present for at least 4 years. She described dark spots confined to the lower legs that had gradually increased in size. Review of systems was negative for fever, chills, night sweats, weight loss, vision changes, cough, dyspnea, and joint pains, and there was no history of either personal or familial cutaneous diseases.

Physical examination revealed cutaneous patches of thin white scale with a sharp edge in arciform patterns on the lower extremities. Several of these patches were hyperpigmented and xerotic in appearance (Figure 1). The patches were limited to the lower legs, with no other lesions noted.

A punch biopsy of the skin on the right lower leg was performed. Histopathologic analysis showed epidermal compact hyperkeratosis with deep granulomatous infiltration into the subcutaneous tissue (Figures 2A and 2B). At high power, these granulomas were noted to be noncaseating naked granulomas composed of epithelioid histiocytes surrounded by sparse lymphocytic inflammation (Figure 2C). Special stains including acid-fast bacilli, Fite, and periodic acid–Schiff were negative. The diagnosis of IS was made based on clinical presentation and primarily by histopathologic analysis.

The patient’s cutaneous lesions were treated with fluocinonide ointment 0.05% twice daily. Although she did not notice a dramatic improvement in the plaques, they stabilized in size. Her primary care physician was notified and advised to begin a workup for involvement of other organ systems by sarcoidosis. Her initial evaluation, which included a chest radiograph and electrocardiogram, were unremarkable. Despite multiple attempts to persuade the patient to return for further follow-up, neither dermatology nor her primary care physician were able to complete a full workup.

Comment

Etiology
Although there are several theories regarding the etiology of sarcoidosis, the exact cause remains unknown. The body’s immune response, infectious agents, genetics, and the environment have all been thought to play a role. It has been well established that helper T cell (T_H1) production of interferon and increased levels of tumor necrosis factor propagate the inflammatory response seen in sarcoidosis.³ More recently, T_H17 cells have been found in cutaneous lesions, bronchoalveolar lavage samples, and the blood of patients with sarcoidosis, especially in those with active disease progression.³ Infectious agents such as mycobacteria and propionibacteria DNA or RNA also have been found in sarcoid samples.⁴ Several HLA-DRB1 variants have been associated with an increased incidence of sarcoidosis.⁵

Presentation
Characteristic dermatologic findings of sarcoidosis include macules, papules, nodules, and plaques located on the face, especially the nose, cheeks, and ears, and on the shins or ankles, as well as similar lesions around tattoos or scars. Sarcoid lesions also have been described as angiolupoid, lichenoid, annular, verrucous, ulcerative, and psoriasiform. Here we present an example of the uncommon type, ichthyosiform. Ichthyosiform sarcoidosis is a rare variant described primarily in dark-skinned individuals, a finding supported by both our case and prior reports. Most reported cases have described IS lesions as having a pasted-on appearance, with adherent centers on the extensor surfaces of the lower extremities, head, and/or neck.⁶ Our case follows this descriptive pattern previously reported with adherent patches limited to the lower extremities.

Histopathology
The key histopathologic finding is the presence of noncaseating granulomas on biopsy. Sarcoid “specific” lesions rest on the identification of the noncaseating granulomas, while “nonspecific” lesions such as erythema nodosum fail to demonstrate this finding.¹

Systemic Involvement
The IS type is believed to be an excellent marker for systemic disease, with approximately 95% of reported cases having some form of systemic illness.⁶ Acquired ichthyosis should warrant further investigation for systemic disease. Early recognition could be beneficial for the patient because the ichthyosiform type is believed to precede the diagnosis of systemic disease in most cases by a median of 3 months.⁶

The most common site of internal sarcoid involvement is the lungs, but the lymph nodes, eyes, liver, spleen, heart, and central nervous system also can be involved. Patients can present with nonspecific symptoms such as erythema nodosum in the skin, dyspnea, cough, chest pain, vision changes, enlarged lymph nodes, headaches, joint pain, fever, fatigue, weight loss, and malaise. According to a PubMed search of articles indexed for MEDLINE using the term ichthyosiform sarcoidosis, 16 cases have been reported in the English-language literature (eTable).^1,6-14 Of these 16 cases, 3 involved men and 13 involved women. The median age of a patient diagnosed with IS was 37 years. The respiratory system was found to be the most common organ system involved (14 of 16 patients), with hilar adenopathy and restrictive lung disease being the most common findings. Neurologic findings and hepatic involvement also were seen in 3 and 3 patients, respectively. Eight of 16 cases had an elevated serum angiotensin-converting enzyme level. Details of systemic involvement in other cases of IS are listed in the eTable.

Management
Most patients are given topical corticosteroids for their cutaneous lesions, but patients with systemic involvement will likely need some type of systemic immunosuppressive therapy to control their disease. Systemic therapy often is warranted in IS because of reports of rapid progression. Our case differs from these prior reports in the relative stability of the disease at the last patient encounter. Systemic treatment commonly includes oral corticosteroids such as prednisone. Other options, such as hydroxychloroquine, methotrexate, azathioprine, pentoxifylline, thalidomide, cyclophosphamide, cyclosporine, and infliximab, can be considered if other treatments fail.¹³ Ichthyosiform sarcoidosis patients should continue to have regular follow-up to monitor for disease progression.

Differential
When evaluating an acquired ichthyosis, dermatologists can consider other associations such as Hodgkin disease, hypothyroidism, multiple myeloma, carcinomatosis, and chronic malnutrition.¹ Skin biopsy demonstrating granuloma formation also is not specific for sarcoidosis. Other etiologies, such as autoimmune diseases, immunodeficiency disorders, infections, foreign body granulomas, neoplasms, and drug reactions, should be considered.¹⁵ All patients with acquired ichthyosis should undergo a thorough evaluation for internal involvement.

Conclusion

We presented a case of IS, a rare type of sarcoidosis commonly associated with further internal involvement of the respiratory, nervous, or hepatic organ systems. Recognition of an acquired form of ichthyosis and its potential disease associations, including sarcoidosis, is important to improve early detection of any internal disease, allowing prompt initiation of treatment.

Sarcoidosis is a multiorgan, systemic, granulomatous disease that most commonly affects the cutaneous, pulmonary, ocular, and cardiac organ systems. Cutaneous involvement occurs in approximately 20% to 35% of patients, with approximately 25% of patients demonstrating only dermatologic findings.¹ Cutaneous sarcoidosis can have a highly variable presentation. Ichthyosiform sarcoidosis (IS) is a rare form of this disease that has been described as presenting as polygonal adherent scales.² It often is associated with internal organ involvement. We present a case of IS without any organ system involvement at the time of diagnosis. A review of the English-language literature was performed to ascertain the internal organ associations most commonly reported with IS.

Case Report

A 66-year-old black woman presented to dermatology with dark scaly patches noted by her primary care physician to be present on both of the lower extremities. The patient believed they were present for at least 4 years. She described dark spots confined to the lower legs that had gradually increased in size. Review of systems was negative for fever, chills, night sweats, weight loss, vision changes, cough, dyspnea, and joint pains, and there was no history of either personal or familial cutaneous diseases.

Physical examination revealed cutaneous patches of thin white scale with a sharp edge in arciform patterns on the lower extremities. Several of these patches were hyperpigmented and xerotic in appearance (Figure 1). The patches were limited to the lower legs, with no other lesions noted.

A punch biopsy of the skin on the right lower leg was performed. Histopathologic analysis showed epidermal compact hyperkeratosis with deep granulomatous infiltration into the subcutaneous tissue (Figures 2A and 2B). At high power, these granulomas were noted to be noncaseating naked granulomas composed of epithelioid histiocytes surrounded by sparse lymphocytic inflammation (Figure 2C). Special stains including acid-fast bacilli, Fite, and periodic acid–Schiff were negative. The diagnosis of IS was made based on clinical presentation and primarily by histopathologic analysis.

The patient’s cutaneous lesions were treated with fluocinonide ointment 0.05% twice daily. Although she did not notice a dramatic improvement in the plaques, they stabilized in size. Her primary care physician was notified and advised to begin a workup for involvement of other organ systems by sarcoidosis. Her initial evaluation, which included a chest radiograph and electrocardiogram, were unremarkable. Despite multiple attempts to persuade the patient to return for further follow-up, neither dermatology nor her primary care physician were able to complete a full workup.

Comment

Etiology
Although there are several theories regarding the etiology of sarcoidosis, the exact cause remains unknown. The body’s immune response, infectious agents, genetics, and the environment have all been thought to play a role. It has been well established that helper T cell (T_H1) production of interferon and increased levels of tumor necrosis factor propagate the inflammatory response seen in sarcoidosis.³ More recently, T_H17 cells have been found in cutaneous lesions, bronchoalveolar lavage samples, and the blood of patients with sarcoidosis, especially in those with active disease progression.³ Infectious agents such as mycobacteria and propionibacteria DNA or RNA also have been found in sarcoid samples.⁴ Several HLA-DRB1 variants have been associated with an increased incidence of sarcoidosis.⁵

Presentation
Characteristic dermatologic findings of sarcoidosis include macules, papules, nodules, and plaques located on the face, especially the nose, cheeks, and ears, and on the shins or ankles, as well as similar lesions around tattoos or scars. Sarcoid lesions also have been described as angiolupoid, lichenoid, annular, verrucous, ulcerative, and psoriasiform. Here we present an example of the uncommon type, ichthyosiform. Ichthyosiform sarcoidosis is a rare variant described primarily in dark-skinned individuals, a finding supported by both our case and prior reports. Most reported cases have described IS lesions as having a pasted-on appearance, with adherent centers on the extensor surfaces of the lower extremities, head, and/or neck.⁶ Our case follows this descriptive pattern previously reported with adherent patches limited to the lower extremities.

Histopathology
The key histopathologic finding is the presence of noncaseating granulomas on biopsy. Sarcoid “specific” lesions rest on the identification of the noncaseating granulomas, while “nonspecific” lesions such as erythema nodosum fail to demonstrate this finding.¹

Systemic Involvement
The IS type is believed to be an excellent marker for systemic disease, with approximately 95% of reported cases having some form of systemic illness.⁶ Acquired ichthyosis should warrant further investigation for systemic disease. Early recognition could be beneficial for the patient because the ichthyosiform type is believed to precede the diagnosis of systemic disease in most cases by a median of 3 months.⁶

The most common site of internal sarcoid involvement is the lungs, but the lymph nodes, eyes, liver, spleen, heart, and central nervous system also can be involved. Patients can present with nonspecific symptoms such as erythema nodosum in the skin, dyspnea, cough, chest pain, vision changes, enlarged lymph nodes, headaches, joint pain, fever, fatigue, weight loss, and malaise. According to a PubMed search of articles indexed for MEDLINE using the term ichthyosiform sarcoidosis, 16 cases have been reported in the English-language literature (eTable).^1,6-14 Of these 16 cases, 3 involved men and 13 involved women. The median age of a patient diagnosed with IS was 37 years. The respiratory system was found to be the most common organ system involved (14 of 16 patients), with hilar adenopathy and restrictive lung disease being the most common findings. Neurologic findings and hepatic involvement also were seen in 3 and 3 patients, respectively. Eight of 16 cases had an elevated serum angiotensin-converting enzyme level. Details of systemic involvement in other cases of IS are listed in the eTable.

Management
Most patients are given topical corticosteroids for their cutaneous lesions, but patients with systemic involvement will likely need some type of systemic immunosuppressive therapy to control their disease. Systemic therapy often is warranted in IS because of reports of rapid progression. Our case differs from these prior reports in the relative stability of the disease at the last patient encounter. Systemic treatment commonly includes oral corticosteroids such as prednisone. Other options, such as hydroxychloroquine, methotrexate, azathioprine, pentoxifylline, thalidomide, cyclophosphamide, cyclosporine, and infliximab, can be considered if other treatments fail.¹³ Ichthyosiform sarcoidosis patients should continue to have regular follow-up to monitor for disease progression.

Differential
When evaluating an acquired ichthyosis, dermatologists can consider other associations such as Hodgkin disease, hypothyroidism, multiple myeloma, carcinomatosis, and chronic malnutrition.¹ Skin biopsy demonstrating granuloma formation also is not specific for sarcoidosis. Other etiologies, such as autoimmune diseases, immunodeficiency disorders, infections, foreign body granulomas, neoplasms, and drug reactions, should be considered.¹⁵ All patients with acquired ichthyosis should undergo a thorough evaluation for internal involvement.

Conclusion

We presented a case of IS, a rare type of sarcoidosis commonly associated with further internal involvement of the respiratory, nervous, or hepatic organ systems. Recognition of an acquired form of ichthyosis and its potential disease associations, including sarcoidosis, is important to improve early detection of any internal disease, allowing prompt initiation of treatment.

Crizotinib is a multitargeted tyrosine kinase inhibitor that blocks anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (c-Met), and their oncogenic variants ALK fusion proteins or c-Met/hepatocyte growth factor receptor mutant variants.¹ Additionally, crizotinib was approved by the US Food and Drug Administration in 2011 for the treatment of patients with non–small cell lung cancer (NSCLC) whose tumors are echinoderm microtubule-associated proteinlike 4 (EML4)/ALK or ROS1 positive.^2,3 Among unselected populations of patients with NSCLC, the frequency of EML4/ALK rearrangements ranges from 1.5% to 6.7%.¹ Crizotinib is superior to standard chemotherapy in patients with ALK-positive NSCLC.²

In clinical trials, adverse reactions (grades 1 to 4) to crizotinib occurring in at least 25% of patients included visual disturbances, gastrointestinal tract disorders, fatigue, and pitting edema.^1,2,4 Adverse reactions (grades 3 and 4) occurring in more than 5% of patients included elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, dyspnea, pneumonia, and neutropenia.^1,4 Although the incidence of dermatologic adverse reactions is approximately 11%, substantial progression of drug eruptions rarely has been reported.^2,5 We describe a case of lichenoid drug eruption (LDE) that appeared 4 weeks after initiation of crizotinib treatment in a patient with ALK-positive metastatic lung adenocarcinoma.

Case Report

A 61-year-old man presented with a history of ALK-positive NSCLC with lung-to-lung metastasis and pleural seeding treated with a right lower lobectomy and chemotherapy 9 years prior. Chemotherapy was reattempted 5 years later. Targeted therapy with gefitinib was initiated following the lobectomy and 5 years later with erlotinib. The NSCLC was stable, as indicated by computed tomography performed once every 3 or 6 months. After 5 years of treatment, follow-up computed tomography showed slowly growing nodular shadows in the right middle and lower lung fields. Due to this disease progression, treatment with crizotinib (250 mg twice daily) was initiated. Four weeks after the initiation of crizotinib therapy, mild itchy skin eruptions developed on all extremities and the lower lip. He also reported that the skin lesions became more itchy and red with sun exposure. He had no history of drug allergies and denied taking any other medications.

Physical examination revealed multiple brown to violaceous, slightly scaly, flat-topped polygonal papules or plaques on both lower legs (Figure 1A), dorsal hands (Figure 1B), and extensor sites of the elbows, as well as lacelike fine white lines on the lower lip (Figure 1C). There were no nail lesions. The patient’s dermatologic history was unremarkable, except for a few vitiligo lesions on the dorsal hands, extensor sites of the elbows, and mouth angles diagnosed 20 years earlier.

A skin biopsy from the right dorsal hand revealed a lichenoid infiltrate in the superficial dermis composed of lymphocytes, histiocytes and scattered eosinophils, focal parakeratosis, focal hypergranulosis, mild acanthosis, and basal vacuolization (Figure 2A). In addition, some dyskeratotic keratinocytes in the stratum spinosum and granulosum were identified (Figure 2B). The histopathology was consistent with the diagnosis of an LDE. Direct immunofluorescence revealed no globular or cytoid body–like deposits of immunoglobulin, with IgM, IgA, IgG, or C3 in the epidermis, dermis, and basement membrane zone. Routine laboratory studies revealed elevated liver enzymes, including an ALT level of 115 U/L (reference range, 0–40 U/L) and AST level of 60 U/L (reference range, 5–45 U/L). Negative results for the serum hepatitis B surface antigen and anti– hepatitis C virus tests were recorded. The patient had no medical history of alcohol consumption or abnormal liver function tests. The skin lesions were treated with diflucortolone valerate fatty ointment 0.1% twice daily and abnormal liver functions were treated with silymarin (150 mg per cap twice daily). He experienced some improvement.

A causality assessment was performed using the Naranjo Adverse Drug Reaction Probability Scale,^6,7 and we concluded that crizotinib was the possible cause (Naranjo score, 4) of this adverse drug reaction (Table). Because the skin reaction was tolerable and liver enzymes were mildly elevated (ALT, 50 U/L; AST, 48 U/L), the offending drug was continued to benefit the underlying disease. His NSCLC was stable on computed tomography 3 months later.

Comment

The number of indicated uses of crizotinib, an oral small-molecule ALK tyrosine kinase inhibitor for the treatment of NSCLC, has gradually increased, but only a few cases of cutaneous adverse reactions, such as erythema multiforme and severe photosensitivity dermatitis, have been reported.^2,5 Skin toxicity is a common and well-known side effect of other small-molecule tyrosine kinase inhibitors, particularly epidermal growth factor receptor inhibitors.⁸ However, LDE is not commonly associated with small-molecule tyrosine kinase inhibitors, though it has been described in a few patients taking imatinib for chronic myelogenous leukemia and gastrointestinal tract stromal tumors.^9,10

The clinical morphology of LDE may resemble lichen planus, but certain features, such as larger skin lesions, the absence of Wickham striae, and photodistribution, help to differentiate between the two.¹⁰ Histologically, some findings are more common in LDE, including focal parakeratosis, cytoid bodies in the cornified and granular layers, and the presence of eosinophils.¹¹

Our patient developed lichenoid rashes after 1 month of crizotinib therapy. The latency period for developing a medication-induced LDE varies from months to 1 year and is dependent on the dosage, host response, prior exposure, and concomitant drug administration. No additional medications had been added to our patient’s regimen after initiating crizotinib therapy, and he did not take any other known medications. Ultimately, based on the time-event relationship, morphology, distribution, and histopathologic findings, we concluded that our patient developed an LDE due to crizotinib.

Our patient also had a history of vitiligo affecting the hands, elbows, and mouth angles for 20 years. Although there are limited reports of a possible causal link between lichen planus or drug-induced lichen planus eruption and vitiligo,^12-14 we do not think these conditions were associated in our case because the patient’s vitiligo lesions persisted for many years, did not progress, and remained inactive and stable, and there was a lack of co-localization of LDE and vitiligo.

Our patient reported that the skin eruptions worsened after sun exposure. Oser and Janne⁵ also reported a patient with ALK-positive metastatic lung adenocarcinoma who developed severe crizotinib-induced photosensitive rashes. Further accumulation of similar cases and pathophysiological studies will be necessary to clarify whether this photosensitivity dermatitis is caused by ALK inhibition itself or mediated through host-immune mechanisms.⁵

Conclusion

As crizotinib prescriptions for patients with NSCLC are increasing, clinicians should be aware of the possibility of cutaneous LDEs occurring as an adverse effect. Additionally, physicians should treat appropriately to avoid unnecessarily discontinuing a potentially life-saving medication and to improve quality of life for patients with NSCLC who are treated with crizotinib.

Crizotinib is a multitargeted tyrosine kinase inhibitor that blocks anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (c-Met), and their oncogenic variants ALK fusion proteins or c-Met/hepatocyte growth factor receptor mutant variants.¹ Additionally, crizotinib was approved by the US Food and Drug Administration in 2011 for the treatment of patients with non–small cell lung cancer (NSCLC) whose tumors are echinoderm microtubule-associated proteinlike 4 (EML4)/ALK or ROS1 positive.^2,3 Among unselected populations of patients with NSCLC, the frequency of EML4/ALK rearrangements ranges from 1.5% to 6.7%.¹ Crizotinib is superior to standard chemotherapy in patients with ALK-positive NSCLC.²

In clinical trials, adverse reactions (grades 1 to 4) to crizotinib occurring in at least 25% of patients included visual disturbances, gastrointestinal tract disorders, fatigue, and pitting edema.^1,2,4 Adverse reactions (grades 3 and 4) occurring in more than 5% of patients included elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, dyspnea, pneumonia, and neutropenia.^1,4 Although the incidence of dermatologic adverse reactions is approximately 11%, substantial progression of drug eruptions rarely has been reported.^2,5 We describe a case of lichenoid drug eruption (LDE) that appeared 4 weeks after initiation of crizotinib treatment in a patient with ALK-positive metastatic lung adenocarcinoma.

Case Report

A 61-year-old man presented with a history of ALK-positive NSCLC with lung-to-lung metastasis and pleural seeding treated with a right lower lobectomy and chemotherapy 9 years prior. Chemotherapy was reattempted 5 years later. Targeted therapy with gefitinib was initiated following the lobectomy and 5 years later with erlotinib. The NSCLC was stable, as indicated by computed tomography performed once every 3 or 6 months. After 5 years of treatment, follow-up computed tomography showed slowly growing nodular shadows in the right middle and lower lung fields. Due to this disease progression, treatment with crizotinib (250 mg twice daily) was initiated. Four weeks after the initiation of crizotinib therapy, mild itchy skin eruptions developed on all extremities and the lower lip. He also reported that the skin lesions became more itchy and red with sun exposure. He had no history of drug allergies and denied taking any other medications.

Physical examination revealed multiple brown to violaceous, slightly scaly, flat-topped polygonal papules or plaques on both lower legs (Figure 1A), dorsal hands (Figure 1B), and extensor sites of the elbows, as well as lacelike fine white lines on the lower lip (Figure 1C). There were no nail lesions. The patient’s dermatologic history was unremarkable, except for a few vitiligo lesions on the dorsal hands, extensor sites of the elbows, and mouth angles diagnosed 20 years earlier.

A skin biopsy from the right dorsal hand revealed a lichenoid infiltrate in the superficial dermis composed of lymphocytes, histiocytes and scattered eosinophils, focal parakeratosis, focal hypergranulosis, mild acanthosis, and basal vacuolization (Figure 2A). In addition, some dyskeratotic keratinocytes in the stratum spinosum and granulosum were identified (Figure 2B). The histopathology was consistent with the diagnosis of an LDE. Direct immunofluorescence revealed no globular or cytoid body–like deposits of immunoglobulin, with IgM, IgA, IgG, or C3 in the epidermis, dermis, and basement membrane zone. Routine laboratory studies revealed elevated liver enzymes, including an ALT level of 115 U/L (reference range, 0–40 U/L) and AST level of 60 U/L (reference range, 5–45 U/L). Negative results for the serum hepatitis B surface antigen and anti– hepatitis C virus tests were recorded. The patient had no medical history of alcohol consumption or abnormal liver function tests. The skin lesions were treated with diflucortolone valerate fatty ointment 0.1% twice daily and abnormal liver functions were treated with silymarin (150 mg per cap twice daily). He experienced some improvement.

A causality assessment was performed using the Naranjo Adverse Drug Reaction Probability Scale,^6,7 and we concluded that crizotinib was the possible cause (Naranjo score, 4) of this adverse drug reaction (Table). Because the skin reaction was tolerable and liver enzymes were mildly elevated (ALT, 50 U/L; AST, 48 U/L), the offending drug was continued to benefit the underlying disease. His NSCLC was stable on computed tomography 3 months later.

Comment

The number of indicated uses of crizotinib, an oral small-molecule ALK tyrosine kinase inhibitor for the treatment of NSCLC, has gradually increased, but only a few cases of cutaneous adverse reactions, such as erythema multiforme and severe photosensitivity dermatitis, have been reported.^2,5 Skin toxicity is a common and well-known side effect of other small-molecule tyrosine kinase inhibitors, particularly epidermal growth factor receptor inhibitors.⁸ However, LDE is not commonly associated with small-molecule tyrosine kinase inhibitors, though it has been described in a few patients taking imatinib for chronic myelogenous leukemia and gastrointestinal tract stromal tumors.^9,10

The clinical morphology of LDE may resemble lichen planus, but certain features, such as larger skin lesions, the absence of Wickham striae, and photodistribution, help to differentiate between the two.¹⁰ Histologically, some findings are more common in LDE, including focal parakeratosis, cytoid bodies in the cornified and granular layers, and the presence of eosinophils.¹¹

Our patient developed lichenoid rashes after 1 month of crizotinib therapy. The latency period for developing a medication-induced LDE varies from months to 1 year and is dependent on the dosage, host response, prior exposure, and concomitant drug administration. No additional medications had been added to our patient’s regimen after initiating crizotinib therapy, and he did not take any other known medications. Ultimately, based on the time-event relationship, morphology, distribution, and histopathologic findings, we concluded that our patient developed an LDE due to crizotinib.

Our patient also had a history of vitiligo affecting the hands, elbows, and mouth angles for 20 years. Although there are limited reports of a possible causal link between lichen planus or drug-induced lichen planus eruption and vitiligo,^12-14 we do not think these conditions were associated in our case because the patient’s vitiligo lesions persisted for many years, did not progress, and remained inactive and stable, and there was a lack of co-localization of LDE and vitiligo.

Our patient reported that the skin eruptions worsened after sun exposure. Oser and Janne⁵ also reported a patient with ALK-positive metastatic lung adenocarcinoma who developed severe crizotinib-induced photosensitive rashes. Further accumulation of similar cases and pathophysiological studies will be necessary to clarify whether this photosensitivity dermatitis is caused by ALK inhibition itself or mediated through host-immune mechanisms.⁵

Conclusion

As crizotinib prescriptions for patients with NSCLC are increasing, clinicians should be aware of the possibility of cutaneous LDEs occurring as an adverse effect. Additionally, physicians should treat appropriately to avoid unnecessarily discontinuing a potentially life-saving medication and to improve quality of life for patients with NSCLC who are treated with crizotinib.

Crizotinib is a multitargeted tyrosine kinase inhibitor that blocks anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (c-Met), and their oncogenic variants ALK fusion proteins or c-Met/hepatocyte growth factor receptor mutant variants.¹ Additionally, crizotinib was approved by the US Food and Drug Administration in 2011 for the treatment of patients with non–small cell lung cancer (NSCLC) whose tumors are echinoderm microtubule-associated proteinlike 4 (EML4)/ALK or ROS1 positive.^2,3 Among unselected populations of patients with NSCLC, the frequency of EML4/ALK rearrangements ranges from 1.5% to 6.7%.¹ Crizotinib is superior to standard chemotherapy in patients with ALK-positive NSCLC.²

In clinical trials, adverse reactions (grades 1 to 4) to crizotinib occurring in at least 25% of patients included visual disturbances, gastrointestinal tract disorders, fatigue, and pitting edema.^1,2,4 Adverse reactions (grades 3 and 4) occurring in more than 5% of patients included elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, dyspnea, pneumonia, and neutropenia.^1,4 Although the incidence of dermatologic adverse reactions is approximately 11%, substantial progression of drug eruptions rarely has been reported.^2,5 We describe a case of lichenoid drug eruption (LDE) that appeared 4 weeks after initiation of crizotinib treatment in a patient with ALK-positive metastatic lung adenocarcinoma.

Case Report

A 61-year-old man presented with a history of ALK-positive NSCLC with lung-to-lung metastasis and pleural seeding treated with a right lower lobectomy and chemotherapy 9 years prior. Chemotherapy was reattempted 5 years later. Targeted therapy with gefitinib was initiated following the lobectomy and 5 years later with erlotinib. The NSCLC was stable, as indicated by computed tomography performed once every 3 or 6 months. After 5 years of treatment, follow-up computed tomography showed slowly growing nodular shadows in the right middle and lower lung fields. Due to this disease progression, treatment with crizotinib (250 mg twice daily) was initiated. Four weeks after the initiation of crizotinib therapy, mild itchy skin eruptions developed on all extremities and the lower lip. He also reported that the skin lesions became more itchy and red with sun exposure. He had no history of drug allergies and denied taking any other medications.

Physical examination revealed multiple brown to violaceous, slightly scaly, flat-topped polygonal papules or plaques on both lower legs (Figure 1A), dorsal hands (Figure 1B), and extensor sites of the elbows, as well as lacelike fine white lines on the lower lip (Figure 1C). There were no nail lesions. The patient’s dermatologic history was unremarkable, except for a few vitiligo lesions on the dorsal hands, extensor sites of the elbows, and mouth angles diagnosed 20 years earlier.

A skin biopsy from the right dorsal hand revealed a lichenoid infiltrate in the superficial dermis composed of lymphocytes, histiocytes and scattered eosinophils, focal parakeratosis, focal hypergranulosis, mild acanthosis, and basal vacuolization (Figure 2A). In addition, some dyskeratotic keratinocytes in the stratum spinosum and granulosum were identified (Figure 2B). The histopathology was consistent with the diagnosis of an LDE. Direct immunofluorescence revealed no globular or cytoid body–like deposits of immunoglobulin, with IgM, IgA, IgG, or C3 in the epidermis, dermis, and basement membrane zone. Routine laboratory studies revealed elevated liver enzymes, including an ALT level of 115 U/L (reference range, 0–40 U/L) and AST level of 60 U/L (reference range, 5–45 U/L). Negative results for the serum hepatitis B surface antigen and anti– hepatitis C virus tests were recorded. The patient had no medical history of alcohol consumption or abnormal liver function tests. The skin lesions were treated with diflucortolone valerate fatty ointment 0.1% twice daily and abnormal liver functions were treated with silymarin (150 mg per cap twice daily). He experienced some improvement.

A causality assessment was performed using the Naranjo Adverse Drug Reaction Probability Scale,^6,7 and we concluded that crizotinib was the possible cause (Naranjo score, 4) of this adverse drug reaction (Table). Because the skin reaction was tolerable and liver enzymes were mildly elevated (ALT, 50 U/L; AST, 48 U/L), the offending drug was continued to benefit the underlying disease. His NSCLC was stable on computed tomography 3 months later.

Comment

The number of indicated uses of crizotinib, an oral small-molecule ALK tyrosine kinase inhibitor for the treatment of NSCLC, has gradually increased, but only a few cases of cutaneous adverse reactions, such as erythema multiforme and severe photosensitivity dermatitis, have been reported.^2,5 Skin toxicity is a common and well-known side effect of other small-molecule tyrosine kinase inhibitors, particularly epidermal growth factor receptor inhibitors.⁸ However, LDE is not commonly associated with small-molecule tyrosine kinase inhibitors, though it has been described in a few patients taking imatinib for chronic myelogenous leukemia and gastrointestinal tract stromal tumors.^9,10

The clinical morphology of LDE may resemble lichen planus, but certain features, such as larger skin lesions, the absence of Wickham striae, and photodistribution, help to differentiate between the two.¹⁰ Histologically, some findings are more common in LDE, including focal parakeratosis, cytoid bodies in the cornified and granular layers, and the presence of eosinophils.¹¹

Our patient developed lichenoid rashes after 1 month of crizotinib therapy. The latency period for developing a medication-induced LDE varies from months to 1 year and is dependent on the dosage, host response, prior exposure, and concomitant drug administration. No additional medications had been added to our patient’s regimen after initiating crizotinib therapy, and he did not take any other known medications. Ultimately, based on the time-event relationship, morphology, distribution, and histopathologic findings, we concluded that our patient developed an LDE due to crizotinib.

Our patient also had a history of vitiligo affecting the hands, elbows, and mouth angles for 20 years. Although there are limited reports of a possible causal link between lichen planus or drug-induced lichen planus eruption and vitiligo,^12-14 we do not think these conditions were associated in our case because the patient’s vitiligo lesions persisted for many years, did not progress, and remained inactive and stable, and there was a lack of co-localization of LDE and vitiligo.

Our patient reported that the skin eruptions worsened after sun exposure. Oser and Janne⁵ also reported a patient with ALK-positive metastatic lung adenocarcinoma who developed severe crizotinib-induced photosensitive rashes. Further accumulation of similar cases and pathophysiological studies will be necessary to clarify whether this photosensitivity dermatitis is caused by ALK inhibition itself or mediated through host-immune mechanisms.⁵

Conclusion

As crizotinib prescriptions for patients with NSCLC are increasing, clinicians should be aware of the possibility of cutaneous LDEs occurring as an adverse effect. Additionally, physicians should treat appropriately to avoid unnecessarily discontinuing a potentially life-saving medication and to improve quality of life for patients with NSCLC who are treated with crizotinib.

The Diagnosis: X-Linked Ichthyosis

Immunohistochemical staining of a punch biopsy specimen from the left foot with cytokeratin markers AE1/3, 5/6, and 19 showed normal positive uptake. Further workup was recommended, and the patient was referred to genetics for an ichthyosis gene panel. DNA sequencing revealed a c.1121G>A transition in exon 10 of the steroid sulfatase gene, STS, consistent with X-linked ichthyosis (XLI).

X-linked ichthyosis, also known as steroid sulfatase deficiency and X-linked recessive ichthyosis, is a congenital skin disorder classified in 1965 by Wells and Kerr.¹ Ichthyoses are a heterogenous group of acquired and congenital disorders of keratinization that manifest with xerosis, hyperkeratosis, and scaling.² Of more than 20 ichthyoses, XLI is the second most common ichthyosis, with a prevalence of 1 in 6000 males.³ X-linked ichthyosis occurs almost exclusively in males, and although females can be carriers, they rarely exhibit skin manifestations.⁴

X-linked ichthyosis is caused by either a partial or full deletion or mutation in the STS gene on the X chromosome.² The absence of STS activity results in the accumulation of cholesterol sulfate in the stratum corneum, leading to corneocyte cohesion, hyperkeratosis, and impaired skin permeability. The most common clinical phenotype is characterized by polygonal scales concentrated on the upper and lower extremities as well as the trunk (Figure), consistent with our patient's clinical presentation.⁵

X-linked ichthyosis typically presents in the first 6 months of life as generalized desquamation and xerosis that progresses to fine scaling on the trunk and extremities, more commonly and heavily involving the legs; however, the extensor surfaces of the arms also may be affected.⁶ After the neonatal period, fine scaling persists on the trunk and extremities, but scales often become coarser and darker over time. Although scaling is generalized, it typically spares the antecubital and popliteal fossae, palms, soles, and midface. The lateral face, axillae, and neck always remain involved.⁴ The most common extracutaneous manifestations of XLI affect the ocular, genitourinary, and cognitive/behavioral systems. Patients can develop corneal comma-shaped opacities, hypogonadism, cryptorchidism, and an increased risk for testicular cancer. Female carriers may have prolonged delivery of affected neonates.^2,5,7-9 Given the unrelated debilitating neurologic consequences of our patient's presenting subarachnoid hemorrhage, further workup was not pursued into these associations.

Although XLI is most commonly diagnosed in early childhood, it also must be considered in adult patients presenting with severe scaling of the trunk, arms, and legs who have not had prior dermatologic workup. Given the similarity of XLI presentation to other ichthyoses, particularly ichthyosis vulgaris, lamellar ichthyosis, and ichthyosis bullosa of Siemens, genetic analysis is the most accurate diagnostic tool and should be considered in patients with an atypical presentation. Rupioid psoriasis also may be considered and can be confirmed on biopsy. Diagnosis of XLI should prompt symptomatic treatment, genetic counseling, and workup for extracutaneous manifestations.

The Diagnosis: X-Linked Ichthyosis

Immunohistochemical staining of a punch biopsy specimen from the left foot with cytokeratin markers AE1/3, 5/6, and 19 showed normal positive uptake. Further workup was recommended, and the patient was referred to genetics for an ichthyosis gene panel. DNA sequencing revealed a c.1121G>A transition in exon 10 of the steroid sulfatase gene, STS, consistent with X-linked ichthyosis (XLI).

X-linked ichthyosis, also known as steroid sulfatase deficiency and X-linked recessive ichthyosis, is a congenital skin disorder classified in 1965 by Wells and Kerr.¹ Ichthyoses are a heterogenous group of acquired and congenital disorders of keratinization that manifest with xerosis, hyperkeratosis, and scaling.² Of more than 20 ichthyoses, XLI is the second most common ichthyosis, with a prevalence of 1 in 6000 males.³ X-linked ichthyosis occurs almost exclusively in males, and although females can be carriers, they rarely exhibit skin manifestations.⁴

X-linked ichthyosis is caused by either a partial or full deletion or mutation in the STS gene on the X chromosome.² The absence of STS activity results in the accumulation of cholesterol sulfate in the stratum corneum, leading to corneocyte cohesion, hyperkeratosis, and impaired skin permeability. The most common clinical phenotype is characterized by polygonal scales concentrated on the upper and lower extremities as well as the trunk (Figure), consistent with our patient's clinical presentation.⁵

X-linked ichthyosis typically presents in the first 6 months of life as generalized desquamation and xerosis that progresses to fine scaling on the trunk and extremities, more commonly and heavily involving the legs; however, the extensor surfaces of the arms also may be affected.⁶ After the neonatal period, fine scaling persists on the trunk and extremities, but scales often become coarser and darker over time. Although scaling is generalized, it typically spares the antecubital and popliteal fossae, palms, soles, and midface. The lateral face, axillae, and neck always remain involved.⁴ The most common extracutaneous manifestations of XLI affect the ocular, genitourinary, and cognitive/behavioral systems. Patients can develop corneal comma-shaped opacities, hypogonadism, cryptorchidism, and an increased risk for testicular cancer. Female carriers may have prolonged delivery of affected neonates.^2,5,7-9 Given the unrelated debilitating neurologic consequences of our patient's presenting subarachnoid hemorrhage, further workup was not pursued into these associations.

Although XLI is most commonly diagnosed in early childhood, it also must be considered in adult patients presenting with severe scaling of the trunk, arms, and legs who have not had prior dermatologic workup. Given the similarity of XLI presentation to other ichthyoses, particularly ichthyosis vulgaris, lamellar ichthyosis, and ichthyosis bullosa of Siemens, genetic analysis is the most accurate diagnostic tool and should be considered in patients with an atypical presentation. Rupioid psoriasis also may be considered and can be confirmed on biopsy. Diagnosis of XLI should prompt symptomatic treatment, genetic counseling, and workup for extracutaneous manifestations.

The Diagnosis: X-Linked Ichthyosis

Immunohistochemical staining of a punch biopsy specimen from the left foot with cytokeratin markers AE1/3, 5/6, and 19 showed normal positive uptake. Further workup was recommended, and the patient was referred to genetics for an ichthyosis gene panel. DNA sequencing revealed a c.1121G>A transition in exon 10 of the steroid sulfatase gene, STS, consistent with X-linked ichthyosis (XLI).

X-linked ichthyosis, also known as steroid sulfatase deficiency and X-linked recessive ichthyosis, is a congenital skin disorder classified in 1965 by Wells and Kerr.¹ Ichthyoses are a heterogenous group of acquired and congenital disorders of keratinization that manifest with xerosis, hyperkeratosis, and scaling.² Of more than 20 ichthyoses, XLI is the second most common ichthyosis, with a prevalence of 1 in 6000 males.³ X-linked ichthyosis occurs almost exclusively in males, and although females can be carriers, they rarely exhibit skin manifestations.⁴

X-linked ichthyosis is caused by either a partial or full deletion or mutation in the STS gene on the X chromosome.² The absence of STS activity results in the accumulation of cholesterol sulfate in the stratum corneum, leading to corneocyte cohesion, hyperkeratosis, and impaired skin permeability. The most common clinical phenotype is characterized by polygonal scales concentrated on the upper and lower extremities as well as the trunk (Figure), consistent with our patient's clinical presentation.⁵

X-linked ichthyosis typically presents in the first 6 months of life as generalized desquamation and xerosis that progresses to fine scaling on the trunk and extremities, more commonly and heavily involving the legs; however, the extensor surfaces of the arms also may be affected.⁶ After the neonatal period, fine scaling persists on the trunk and extremities, but scales often become coarser and darker over time. Although scaling is generalized, it typically spares the antecubital and popliteal fossae, palms, soles, and midface. The lateral face, axillae, and neck always remain involved.⁴ The most common extracutaneous manifestations of XLI affect the ocular, genitourinary, and cognitive/behavioral systems. Patients can develop corneal comma-shaped opacities, hypogonadism, cryptorchidism, and an increased risk for testicular cancer. Female carriers may have prolonged delivery of affected neonates.^2,5,7-9 Given the unrelated debilitating neurologic consequences of our patient's presenting subarachnoid hemorrhage, further workup was not pursued into these associations.

Although XLI is most commonly diagnosed in early childhood, it also must be considered in adult patients presenting with severe scaling of the trunk, arms, and legs who have not had prior dermatologic workup. Given the similarity of XLI presentation to other ichthyoses, particularly ichthyosis vulgaris, lamellar ichthyosis, and ichthyosis bullosa of Siemens, genetic analysis is the most accurate diagnostic tool and should be considered in patients with an atypical presentation. Rupioid psoriasis also may be considered and can be confirmed on biopsy. Diagnosis of XLI should prompt symptomatic treatment, genetic counseling, and workup for extracutaneous manifestations.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.

Onychomycosis is a fungal infection of the nail unit due to dermatophytes, yeasts, and nondermatophyte molds (NDMs). It accounts for approximately 50% of all nail disorders seen in clinical practice and is estimated to affect 10% to 12% of the US population.^1,2 Oral medications approved by the US Food and Drug Administration (FDA) include terbinafine and itraconazole, which have demonstrated good efficacy in treating onychomycosis but are associated with potential drug-drug interactions and systemic side effects.^3,4 Although liver failure associated with these drugs is rare,⁵ many patients are anxious about systemic adverse events and therefore prefer to use topical therapies for onychomycosis.

Many patients desire topical therapy but not every patient is an appropriate candidate. Patients who will likely respond well to topical therapy include those with superficial onychomycosis, distal lateral subungual onychomycosis that involves less than 50% of the nail plate surface area (without matrix involvement and a nail plate thickness less than 2 mm), and only up to 3 or 4 nails affected.⁶ In patients who have contraindications to oral therapy, topical therapy may be the only treatment option. To maximize efficacy of FDA-approved topical agents for onychomycosis therapy, patient education is of utmost importance. Failure to properly counsel the patient on proper medication application may result in decreased antifungal efficacy; poor patient compliance due to lack of improvement; and progression of disease, leading to increased onychodystrophy and pain.

Before initiating therapy, patients should be counseled that treatment with topical drugs is long, requiring daily application of the medication for 6 months for fingernails and 12 months for toenails, based on average nail growth rates (2–3 mm per month for fingernails; 1 mm per month for toenails).⁷ Patients also are advised to avoid nail polish application during the course of therapy, as clinical trials were performed without nail polish and the true efficacy with nail polish is unknown.^8-10 Because patients who have had onychomycosis for shorter durations generally have better cure rates than those who have disease for longer durations, it is prudent to initiate topical therapy as early as possible.^11,12 Treating the feet with an antifungal while treating the nails for onychomycosis further enhances efficacy.^13,14 There are 3 FDA-approved topical therapies for onychomycosis: ciclopirox nail lacquer 8%, efinaconazole solution 10%, and tavaborole solution 5%.^15-17

Ciclopirox is a hydroxypyridone with broad-spectrum antimicrobial activity against dermatophytes, NDMs, yeasts, and bacteria. Its mechanism of action is to chelate polyvalent cations, such as Fe³⁺, and inhibit fungal metal-dependent enzymes responsible for the degradation of toxic metabolites.¹⁵ Ciclopirox nail lacquer 8% was FDA approved for the treatment of onychomycosis in 1999, making it the first topical approved for this purpose. Its indication is for immunocompetent patients with mild to moderate onychomycosis (Trichophyton rubrum) without lunula involvement, with mycologic cure rates of 29% to 36% and complete cure rates of 5.5% to 8.5% (toenails).¹⁵ It is the only FDA-approved topical treatment for both fingernails and toenails. Using a brush applicator, it is applied daily to the nail plate and its undersurface, hyponychium, and 5 mm of the surrounding skin. It is important to counsel the patient to remove the lacquer from the nail plate weekly because failure to do so will result in accumulation of numerous layers of medication, such that the active drug cannot reach the site of infection (Figures 1 and 2). The nail plate also should be trimmed and filed weekly by the patient, with monthly clipping/debridement by a physician recommended.^6,15

Efinaconazole is a triazole with antifungal activity against dermatophytes, NDMs, and Candida species. Its mechanism of action is inhibition of lanosterol 14α-demethylase, an enzyme involved in the biosynthesis of ergosterol, which is a component of the fungal cell membrane. Efinaconazole solution 10% was FDA approved in June 2014 for the treatment of toenail onychomycosis due to T rubrum and Trichophyton mentagrophytes, with package insert mycologic cure rates of 53.4% to 55.2% and complete cure rates of 15.2% to 17.8%.^9,16 It is applied with a brush applicator to the nail plate, as well as its undersurface, nail folds, and hyponychium. Two drops are recommended for the great toenail and one drop for all other toenails, and no removal of the solution or debridement is required.^6,16

Tavaborole is a benzoxaborole with antifungal activity against dermatophytes, NDMs, and yeasts. Its mechanism of action is inhibition of fungal aminoacyl transfer RNA synthetase, thus impeding protein synthesis.¹⁸ Tavaborole solution 5% was FDA approved in July 2014 for the treatment of toenail onychomycosis due to T rubrum and T mentagrophytes, with mycologic cure rates of 31.1% and 35.9% and complete cure rates of 6.5% and 9.1%, respectively.^11,17 It is applied with a glass pointed-tip dropper to the nail plate, such that the entire nail is covered as well as under the nail tip. No removal of the solution or debridement is required.¹⁷

Topical therapies for onychomycosis require long treatment durations, thus excellent compliance and adherence to the treatment protocol are vital to maximize efficacy. Dermatologists who prescribe ciclopirox nail lacquer 8% should counsel patients to remove the lacquer with alcohol weekly, such that the antifungal penetrates the nail plate to reach the site of infection. Monthly debridement also must be clarified before initiating therapy. With all topical therapy for onychomycosis, it is important to treat early, treat concurrently for tinea pedis, and avoid use of nail polish so that patients have the best possible cure rates.

Onychomycosis is a fungal infection of the nail unit due to dermatophytes, yeasts, and nondermatophyte molds (NDMs). It accounts for approximately 50% of all nail disorders seen in clinical practice and is estimated to affect 10% to 12% of the US population.^1,2 Oral medications approved by the US Food and Drug Administration (FDA) include terbinafine and itraconazole, which have demonstrated good efficacy in treating onychomycosis but are associated with potential drug-drug interactions and systemic side effects.^3,4 Although liver failure associated with these drugs is rare,⁵ many patients are anxious about systemic adverse events and therefore prefer to use topical therapies for onychomycosis.

Many patients desire topical therapy but not every patient is an appropriate candidate. Patients who will likely respond well to topical therapy include those with superficial onychomycosis, distal lateral subungual onychomycosis that involves less than 50% of the nail plate surface area (without matrix involvement and a nail plate thickness less than 2 mm), and only up to 3 or 4 nails affected.⁶ In patients who have contraindications to oral therapy, topical therapy may be the only treatment option. To maximize efficacy of FDA-approved topical agents for onychomycosis therapy, patient education is of utmost importance. Failure to properly counsel the patient on proper medication application may result in decreased antifungal efficacy; poor patient compliance due to lack of improvement; and progression of disease, leading to increased onychodystrophy and pain.

Before initiating therapy, patients should be counseled that treatment with topical drugs is long, requiring daily application of the medication for 6 months for fingernails and 12 months for toenails, based on average nail growth rates (2–3 mm per month for fingernails; 1 mm per month for toenails).⁷ Patients also are advised to avoid nail polish application during the course of therapy, as clinical trials were performed without nail polish and the true efficacy with nail polish is unknown.^8-10 Because patients who have had onychomycosis for shorter durations generally have better cure rates than those who have disease for longer durations, it is prudent to initiate topical therapy as early as possible.^11,12 Treating the feet with an antifungal while treating the nails for onychomycosis further enhances efficacy.^13,14 There are 3 FDA-approved topical therapies for onychomycosis: ciclopirox nail lacquer 8%, efinaconazole solution 10%, and tavaborole solution 5%.^15-17

Ciclopirox is a hydroxypyridone with broad-spectrum antimicrobial activity against dermatophytes, NDMs, yeasts, and bacteria. Its mechanism of action is to chelate polyvalent cations, such as Fe³⁺, and inhibit fungal metal-dependent enzymes responsible for the degradation of toxic metabolites.¹⁵ Ciclopirox nail lacquer 8% was FDA approved for the treatment of onychomycosis in 1999, making it the first topical approved for this purpose. Its indication is for immunocompetent patients with mild to moderate onychomycosis (Trichophyton rubrum) without lunula involvement, with mycologic cure rates of 29% to 36% and complete cure rates of 5.5% to 8.5% (toenails).¹⁵ It is the only FDA-approved topical treatment for both fingernails and toenails. Using a brush applicator, it is applied daily to the nail plate and its undersurface, hyponychium, and 5 mm of the surrounding skin. It is important to counsel the patient to remove the lacquer from the nail plate weekly because failure to do so will result in accumulation of numerous layers of medication, such that the active drug cannot reach the site of infection (Figures 1 and 2). The nail plate also should be trimmed and filed weekly by the patient, with monthly clipping/debridement by a physician recommended.^6,15

Efinaconazole is a triazole with antifungal activity against dermatophytes, NDMs, and Candida species. Its mechanism of action is inhibition of lanosterol 14α-demethylase, an enzyme involved in the biosynthesis of ergosterol, which is a component of the fungal cell membrane. Efinaconazole solution 10% was FDA approved in June 2014 for the treatment of toenail onychomycosis due to T rubrum and Trichophyton mentagrophytes, with package insert mycologic cure rates of 53.4% to 55.2% and complete cure rates of 15.2% to 17.8%.^9,16 It is applied with a brush applicator to the nail plate, as well as its undersurface, nail folds, and hyponychium. Two drops are recommended for the great toenail and one drop for all other toenails, and no removal of the solution or debridement is required.^6,16

Tavaborole is a benzoxaborole with antifungal activity against dermatophytes, NDMs, and yeasts. Its mechanism of action is inhibition of fungal aminoacyl transfer RNA synthetase, thus impeding protein synthesis.¹⁸ Tavaborole solution 5% was FDA approved in July 2014 for the treatment of toenail onychomycosis due to T rubrum and T mentagrophytes, with mycologic cure rates of 31.1% and 35.9% and complete cure rates of 6.5% and 9.1%, respectively.^11,17 It is applied with a glass pointed-tip dropper to the nail plate, such that the entire nail is covered as well as under the nail tip. No removal of the solution or debridement is required.¹⁷

Topical therapies for onychomycosis require long treatment durations, thus excellent compliance and adherence to the treatment protocol are vital to maximize efficacy. Dermatologists who prescribe ciclopirox nail lacquer 8% should counsel patients to remove the lacquer with alcohol weekly, such that the antifungal penetrates the nail plate to reach the site of infection. Monthly debridement also must be clarified before initiating therapy. With all topical therapy for onychomycosis, it is important to treat early, treat concurrently for tinea pedis, and avoid use of nail polish so that patients have the best possible cure rates.

Onychomycosis is a fungal infection of the nail unit due to dermatophytes, yeasts, and nondermatophyte molds (NDMs). It accounts for approximately 50% of all nail disorders seen in clinical practice and is estimated to affect 10% to 12% of the US population.^1,2 Oral medications approved by the US Food and Drug Administration (FDA) include terbinafine and itraconazole, which have demonstrated good efficacy in treating onychomycosis but are associated with potential drug-drug interactions and systemic side effects.^3,4 Although liver failure associated with these drugs is rare,⁵ many patients are anxious about systemic adverse events and therefore prefer to use topical therapies for onychomycosis.

Many patients desire topical therapy but not every patient is an appropriate candidate. Patients who will likely respond well to topical therapy include those with superficial onychomycosis, distal lateral subungual onychomycosis that involves less than 50% of the nail plate surface area (without matrix involvement and a nail plate thickness less than 2 mm), and only up to 3 or 4 nails affected.⁶ In patients who have contraindications to oral therapy, topical therapy may be the only treatment option. To maximize efficacy of FDA-approved topical agents for onychomycosis therapy, patient education is of utmost importance. Failure to properly counsel the patient on proper medication application may result in decreased antifungal efficacy; poor patient compliance due to lack of improvement; and progression of disease, leading to increased onychodystrophy and pain.

Before initiating therapy, patients should be counseled that treatment with topical drugs is long, requiring daily application of the medication for 6 months for fingernails and 12 months for toenails, based on average nail growth rates (2–3 mm per month for fingernails; 1 mm per month for toenails).⁷ Patients also are advised to avoid nail polish application during the course of therapy, as clinical trials were performed without nail polish and the true efficacy with nail polish is unknown.^8-10 Because patients who have had onychomycosis for shorter durations generally have better cure rates than those who have disease for longer durations, it is prudent to initiate topical therapy as early as possible.^11,12 Treating the feet with an antifungal while treating the nails for onychomycosis further enhances efficacy.^13,14 There are 3 FDA-approved topical therapies for onychomycosis: ciclopirox nail lacquer 8%, efinaconazole solution 10%, and tavaborole solution 5%.^15-17

Ciclopirox is a hydroxypyridone with broad-spectrum antimicrobial activity against dermatophytes, NDMs, yeasts, and bacteria. Its mechanism of action is to chelate polyvalent cations, such as Fe³⁺, and inhibit fungal metal-dependent enzymes responsible for the degradation of toxic metabolites.¹⁵ Ciclopirox nail lacquer 8% was FDA approved for the treatment of onychomycosis in 1999, making it the first topical approved for this purpose. Its indication is for immunocompetent patients with mild to moderate onychomycosis (Trichophyton rubrum) without lunula involvement, with mycologic cure rates of 29% to 36% and complete cure rates of 5.5% to 8.5% (toenails).¹⁵ It is the only FDA-approved topical treatment for both fingernails and toenails. Using a brush applicator, it is applied daily to the nail plate and its undersurface, hyponychium, and 5 mm of the surrounding skin. It is important to counsel the patient to remove the lacquer from the nail plate weekly because failure to do so will result in accumulation of numerous layers of medication, such that the active drug cannot reach the site of infection (Figures 1 and 2). The nail plate also should be trimmed and filed weekly by the patient, with monthly clipping/debridement by a physician recommended.^6,15

Efinaconazole is a triazole with antifungal activity against dermatophytes, NDMs, and Candida species. Its mechanism of action is inhibition of lanosterol 14α-demethylase, an enzyme involved in the biosynthesis of ergosterol, which is a component of the fungal cell membrane. Efinaconazole solution 10% was FDA approved in June 2014 for the treatment of toenail onychomycosis due to T rubrum and Trichophyton mentagrophytes, with package insert mycologic cure rates of 53.4% to 55.2% and complete cure rates of 15.2% to 17.8%.^9,16 It is applied with a brush applicator to the nail plate, as well as its undersurface, nail folds, and hyponychium. Two drops are recommended for the great toenail and one drop for all other toenails, and no removal of the solution or debridement is required.^6,16

Tavaborole is a benzoxaborole with antifungal activity against dermatophytes, NDMs, and yeasts. Its mechanism of action is inhibition of fungal aminoacyl transfer RNA synthetase, thus impeding protein synthesis.¹⁸ Tavaborole solution 5% was FDA approved in July 2014 for the treatment of toenail onychomycosis due to T rubrum and T mentagrophytes, with mycologic cure rates of 31.1% and 35.9% and complete cure rates of 6.5% and 9.1%, respectively.^11,17 It is applied with a glass pointed-tip dropper to the nail plate, such that the entire nail is covered as well as under the nail tip. No removal of the solution or debridement is required.¹⁷

Topical therapies for onychomycosis require long treatment durations, thus excellent compliance and adherence to the treatment protocol are vital to maximize efficacy. Dermatologists who prescribe ciclopirox nail lacquer 8% should counsel patients to remove the lacquer with alcohol weekly, such that the antifungal penetrates the nail plate to reach the site of infection. Monthly debridement also must be clarified before initiating therapy. With all topical therapy for onychomycosis, it is important to treat early, treat concurrently for tinea pedis, and avoid use of nail polish so that patients have the best possible cure rates.

Perusal of any lifestyle magazine reveals photographs of movie stars with sun-kissed skin. One can imagine their carefree lives afford ample time outdoors, a vast departure from the pasty masses trapped in their office cubicles. Our cultural norms dictate that a glowing look is a sign of health and attractiveness. Light-skinned individuals must receive regular exposure to sunlight to maintain their bronzed color. Over the last century, the indoor tanning industry has expanded to fill the niche created by the ceaseless pursuit of the ideal complexion.

Indoor tanning use causes up to 170,000 cases of skin cancer per year worldwide.¹ Accumulating sunburns early in life is a leading risk factor for melanoma, the deadliest form of skin cancer. Campaigns to spread awareness about the link between UV radiation and skin cancer are ubiquitous. The US Food and Drug Administration (FDA) recommends against the use of tanning beds by minors, and several states have passed laws restricting their access. However, adolescents continue to engage. White female high school students remain frequenters of this practice, with more than 15% reporting current use of indoor tanning facilities.² It seems targeted outreach and media campaigns are unsuccessful in influencing their behavior, and new approaches are needed.

Tanning-Related Injuries

Concentrated exposure to UV radiation during indoor tanning sessions carries the potential for immediate harm. Public health campaigns have focused on long-term skin cancer risk while overlooking thousands of injuries that occur annually at tanning salons across the country. The US Consumer Product Safety Commission first noted injuries associated with the largely unregulated tanning industry in 1974.³ In response, the FDA limited radiation levels, required indoor tanning devices to have timers and manual off switches, and mandated the use of protective eyewear. These changes sparked industry backlash due to the cost of compliance. The Indoor Tanning Association (no longer in operation) hired a lobbying firm in 2009 that successfully fought to resist further regulation.³

More than 3000 indoor tanning–related injuries are treated in emergency departments annually.⁴ White women aged 18 to 24 years who visit tanning salons are most likely to sustain injuries. In one study, severe skin burns accounted for 80% of emergency department visits, while the rest were due to fainting, eye injuries, and infections from unsanitary equipment.Timer malfunctions may play a role in tanning bed injuries, as several injured patients have reported falling asleep while tanning.⁴ Only 5% of tanning salons in North Carolina complied with FDA-recommended exposure schedules in 2003, suggesting that neglect or deliberate override of safety features also may contribute to injury.⁵

Challenges in Changing Tanning Behaviors

Use of indoor tanning facilities by adolescents is boosted by their misperceptions of peer engagement. Many teenagers overestimate the number of their peers who tan, which influences their own behavior.⁶ This phenomenon illustrates the importance of perceived social norms in this demographic group. Motivating adolescents to take actions that violate these norms poses a considerable challenge.

To teenagers, the perceived immediate benefits of indoor tanning far outweigh perceived costs. The immediate benefit of indoor tanning is having attractive skin, which may improve social standing and perceived self-worth. When adolescents weigh costs and benefits at different points in time, the present value of future events is discounted when compared to current events. For example, an immediate loss of $1000 is more impactful than losing $1000 ten years down the road. Adolescents are motivated to succeed in the short-term and may heavily discount future adverse effects such as the risk for developing cancer or premature aging of the skin. Therefore, getting a tan may be the “rational” decision even if there is an increased risk of future skin cancer.⁷

The addiction theory of tanning seeks to explain why individuals continue to tan despite knowledge of the associated risks. Exposure to UV radiation releases endorphins, producing a natural narcotic effect.⁸ The relaxing feeling sunbathers experience may lead to a phenomenon similar to addictions to opioids, alcohol, tobacco, and sugar. Behavior change is a process that unfolds over time. The 5 stages are precontemplation, contemplation, preparation, action, and maintenance.⁹ Education falls on deaf ears when the recipients are not ready to consider change. Individuals who are already thinking about cutting back on tanning fall into the category of contemplators and are the most open to educational techniques.⁹

Potential Solutions

Despite the dire long-term consequences of melanoma, warning adolescents of the increased cancer risk from tanning is an ineffective dissuasion strategy.¹⁰ Solutions that aim to limit tanning behaviors in this population should instead center on decreasing the present utility of a tan. Emphasis on the risk of immediate injury may be one effective route. The costs of potential damage to current appearance, vision, and overall health are not readily discounted by adolescents. Teens who devote time and money to the pursuit of a golden glow place high value on attractiveness. Such individuals respond best to loss-framed messages that focus on the impact of UV exposure on appearance, not just their health.¹¹ However, appearance-motivated individuals may feel threatened by interventions that aim to reduce their decision freedom and display high reactance, leading them to reassert their freedom by resisting antitanning messages.¹² Another strategy is altering media messaging to support a wider swathe of skin tones, reducing the social benefits of a tan. To swing the needle on our cultural norms, this intervention will require an enduring effort with backing from media outlets and celebrities.

Taxes on tanning salons and devices provide a basic economic disincentive to adolescents who typically have limited funds. State cigarette tax increases successfully reduced youth consumption of tobacco in the 1990s.¹³ A provision of the Patient Protection and Affordable Care Act levied a 10% excise tax on tanning salons with promising early results.¹⁴ Further taxation may generate revenue for educational campaigns on the injury risks of tanning. Continued safety improvements that limit user exposure to UV radiation and enforcement of FDA regulations also will decrease injury rates. Minimizing the UV output of tanning beds and designing protective equipment for tanners are 2 potential objectives. Improvement of over-the-counter sunless tanning agents also will provide alternatives to catching rays for adolescents who wish to attain a bronzed complexion.

Final Thoughts

Health care providers must assess a patient’s readiness for change and tailor interventions accordingly. Regardless of the method, new approaches to combat adolescent tanning injuries may reduce health care costs and minimize serious public health concerns for the next generation.

Perusal of any lifestyle magazine reveals photographs of movie stars with sun-kissed skin. One can imagine their carefree lives afford ample time outdoors, a vast departure from the pasty masses trapped in their office cubicles. Our cultural norms dictate that a glowing look is a sign of health and attractiveness. Light-skinned individuals must receive regular exposure to sunlight to maintain their bronzed color. Over the last century, the indoor tanning industry has expanded to fill the niche created by the ceaseless pursuit of the ideal complexion.

Indoor tanning use causes up to 170,000 cases of skin cancer per year worldwide.¹ Accumulating sunburns early in life is a leading risk factor for melanoma, the deadliest form of skin cancer. Campaigns to spread awareness about the link between UV radiation and skin cancer are ubiquitous. The US Food and Drug Administration (FDA) recommends against the use of tanning beds by minors, and several states have passed laws restricting their access. However, adolescents continue to engage. White female high school students remain frequenters of this practice, with more than 15% reporting current use of indoor tanning facilities.² It seems targeted outreach and media campaigns are unsuccessful in influencing their behavior, and new approaches are needed.

Tanning-Related Injuries

Concentrated exposure to UV radiation during indoor tanning sessions carries the potential for immediate harm. Public health campaigns have focused on long-term skin cancer risk while overlooking thousands of injuries that occur annually at tanning salons across the country. The US Consumer Product Safety Commission first noted injuries associated with the largely unregulated tanning industry in 1974.³ In response, the FDA limited radiation levels, required indoor tanning devices to have timers and manual off switches, and mandated the use of protective eyewear. These changes sparked industry backlash due to the cost of compliance. The Indoor Tanning Association (no longer in operation) hired a lobbying firm in 2009 that successfully fought to resist further regulation.³

More than 3000 indoor tanning–related injuries are treated in emergency departments annually.⁴ White women aged 18 to 24 years who visit tanning salons are most likely to sustain injuries. In one study, severe skin burns accounted for 80% of emergency department visits, while the rest were due to fainting, eye injuries, and infections from unsanitary equipment.Timer malfunctions may play a role in tanning bed injuries, as several injured patients have reported falling asleep while tanning.⁴ Only 5% of tanning salons in North Carolina complied with FDA-recommended exposure schedules in 2003, suggesting that neglect or deliberate override of safety features also may contribute to injury.⁵

Challenges in Changing Tanning Behaviors

Use of indoor tanning facilities by adolescents is boosted by their misperceptions of peer engagement. Many teenagers overestimate the number of their peers who tan, which influences their own behavior.⁶ This phenomenon illustrates the importance of perceived social norms in this demographic group. Motivating adolescents to take actions that violate these norms poses a considerable challenge.

To teenagers, the perceived immediate benefits of indoor tanning far outweigh perceived costs. The immediate benefit of indoor tanning is having attractive skin, which may improve social standing and perceived self-worth. When adolescents weigh costs and benefits at different points in time, the present value of future events is discounted when compared to current events. For example, an immediate loss of $1000 is more impactful than losing $1000 ten years down the road. Adolescents are motivated to succeed in the short-term and may heavily discount future adverse effects such as the risk for developing cancer or premature aging of the skin. Therefore, getting a tan may be the “rational” decision even if there is an increased risk of future skin cancer.⁷

The addiction theory of tanning seeks to explain why individuals continue to tan despite knowledge of the associated risks. Exposure to UV radiation releases endorphins, producing a natural narcotic effect.⁸ The relaxing feeling sunbathers experience may lead to a phenomenon similar to addictions to opioids, alcohol, tobacco, and sugar. Behavior change is a process that unfolds over time. The 5 stages are precontemplation, contemplation, preparation, action, and maintenance.⁹ Education falls on deaf ears when the recipients are not ready to consider change. Individuals who are already thinking about cutting back on tanning fall into the category of contemplators and are the most open to educational techniques.⁹

Potential Solutions

Despite the dire long-term consequences of melanoma, warning adolescents of the increased cancer risk from tanning is an ineffective dissuasion strategy.¹⁰ Solutions that aim to limit tanning behaviors in this population should instead center on decreasing the present utility of a tan. Emphasis on the risk of immediate injury may be one effective route. The costs of potential damage to current appearance, vision, and overall health are not readily discounted by adolescents. Teens who devote time and money to the pursuit of a golden glow place high value on attractiveness. Such individuals respond best to loss-framed messages that focus on the impact of UV exposure on appearance, not just their health.¹¹ However, appearance-motivated individuals may feel threatened by interventions that aim to reduce their decision freedom and display high reactance, leading them to reassert their freedom by resisting antitanning messages.¹² Another strategy is altering media messaging to support a wider swathe of skin tones, reducing the social benefits of a tan. To swing the needle on our cultural norms, this intervention will require an enduring effort with backing from media outlets and celebrities.

Taxes on tanning salons and devices provide a basic economic disincentive to adolescents who typically have limited funds. State cigarette tax increases successfully reduced youth consumption of tobacco in the 1990s.¹³ A provision of the Patient Protection and Affordable Care Act levied a 10% excise tax on tanning salons with promising early results.¹⁴ Further taxation may generate revenue for educational campaigns on the injury risks of tanning. Continued safety improvements that limit user exposure to UV radiation and enforcement of FDA regulations also will decrease injury rates. Minimizing the UV output of tanning beds and designing protective equipment for tanners are 2 potential objectives. Improvement of over-the-counter sunless tanning agents also will provide alternatives to catching rays for adolescents who wish to attain a bronzed complexion.

Final Thoughts

Health care providers must assess a patient’s readiness for change and tailor interventions accordingly. Regardless of the method, new approaches to combat adolescent tanning injuries may reduce health care costs and minimize serious public health concerns for the next generation.

Perusal of any lifestyle magazine reveals photographs of movie stars with sun-kissed skin. One can imagine their carefree lives afford ample time outdoors, a vast departure from the pasty masses trapped in their office cubicles. Our cultural norms dictate that a glowing look is a sign of health and attractiveness. Light-skinned individuals must receive regular exposure to sunlight to maintain their bronzed color. Over the last century, the indoor tanning industry has expanded to fill the niche created by the ceaseless pursuit of the ideal complexion.

Indoor tanning use causes up to 170,000 cases of skin cancer per year worldwide.¹ Accumulating sunburns early in life is a leading risk factor for melanoma, the deadliest form of skin cancer. Campaigns to spread awareness about the link between UV radiation and skin cancer are ubiquitous. The US Food and Drug Administration (FDA) recommends against the use of tanning beds by minors, and several states have passed laws restricting their access. However, adolescents continue to engage. White female high school students remain frequenters of this practice, with more than 15% reporting current use of indoor tanning facilities.² It seems targeted outreach and media campaigns are unsuccessful in influencing their behavior, and new approaches are needed.

Tanning-Related Injuries

Concentrated exposure to UV radiation during indoor tanning sessions carries the potential for immediate harm. Public health campaigns have focused on long-term skin cancer risk while overlooking thousands of injuries that occur annually at tanning salons across the country. The US Consumer Product Safety Commission first noted injuries associated with the largely unregulated tanning industry in 1974.³ In response, the FDA limited radiation levels, required indoor tanning devices to have timers and manual off switches, and mandated the use of protective eyewear. These changes sparked industry backlash due to the cost of compliance. The Indoor Tanning Association (no longer in operation) hired a lobbying firm in 2009 that successfully fought to resist further regulation.³

More than 3000 indoor tanning–related injuries are treated in emergency departments annually.⁴ White women aged 18 to 24 years who visit tanning salons are most likely to sustain injuries. In one study, severe skin burns accounted for 80% of emergency department visits, while the rest were due to fainting, eye injuries, and infections from unsanitary equipment.Timer malfunctions may play a role in tanning bed injuries, as several injured patients have reported falling asleep while tanning.⁴ Only 5% of tanning salons in North Carolina complied with FDA-recommended exposure schedules in 2003, suggesting that neglect or deliberate override of safety features also may contribute to injury.⁵

Challenges in Changing Tanning Behaviors

Use of indoor tanning facilities by adolescents is boosted by their misperceptions of peer engagement. Many teenagers overestimate the number of their peers who tan, which influences their own behavior.⁶ This phenomenon illustrates the importance of perceived social norms in this demographic group. Motivating adolescents to take actions that violate these norms poses a considerable challenge.

To teenagers, the perceived immediate benefits of indoor tanning far outweigh perceived costs. The immediate benefit of indoor tanning is having attractive skin, which may improve social standing and perceived self-worth. When adolescents weigh costs and benefits at different points in time, the present value of future events is discounted when compared to current events. For example, an immediate loss of $1000 is more impactful than losing $1000 ten years down the road. Adolescents are motivated to succeed in the short-term and may heavily discount future adverse effects such as the risk for developing cancer or premature aging of the skin. Therefore, getting a tan may be the “rational” decision even if there is an increased risk of future skin cancer.⁷

The addiction theory of tanning seeks to explain why individuals continue to tan despite knowledge of the associated risks. Exposure to UV radiation releases endorphins, producing a natural narcotic effect.⁸ The relaxing feeling sunbathers experience may lead to a phenomenon similar to addictions to opioids, alcohol, tobacco, and sugar. Behavior change is a process that unfolds over time. The 5 stages are precontemplation, contemplation, preparation, action, and maintenance.⁹ Education falls on deaf ears when the recipients are not ready to consider change. Individuals who are already thinking about cutting back on tanning fall into the category of contemplators and are the most open to educational techniques.⁹

Potential Solutions

Despite the dire long-term consequences of melanoma, warning adolescents of the increased cancer risk from tanning is an ineffective dissuasion strategy.¹⁰ Solutions that aim to limit tanning behaviors in this population should instead center on decreasing the present utility of a tan. Emphasis on the risk of immediate injury may be one effective route. The costs of potential damage to current appearance, vision, and overall health are not readily discounted by adolescents. Teens who devote time and money to the pursuit of a golden glow place high value on attractiveness. Such individuals respond best to loss-framed messages that focus on the impact of UV exposure on appearance, not just their health.¹¹ However, appearance-motivated individuals may feel threatened by interventions that aim to reduce their decision freedom and display high reactance, leading them to reassert their freedom by resisting antitanning messages.¹² Another strategy is altering media messaging to support a wider swathe of skin tones, reducing the social benefits of a tan. To swing the needle on our cultural norms, this intervention will require an enduring effort with backing from media outlets and celebrities.

Taxes on tanning salons and devices provide a basic economic disincentive to adolescents who typically have limited funds. State cigarette tax increases successfully reduced youth consumption of tobacco in the 1990s.¹³ A provision of the Patient Protection and Affordable Care Act levied a 10% excise tax on tanning salons with promising early results.¹⁴ Further taxation may generate revenue for educational campaigns on the injury risks of tanning. Continued safety improvements that limit user exposure to UV radiation and enforcement of FDA regulations also will decrease injury rates. Minimizing the UV output of tanning beds and designing protective equipment for tanners are 2 potential objectives. Improvement of over-the-counter sunless tanning agents also will provide alternatives to catching rays for adolescents who wish to attain a bronzed complexion.

Final Thoughts

Health care providers must assess a patient’s readiness for change and tailor interventions accordingly. Regardless of the method, new approaches to combat adolescent tanning injuries may reduce health care costs and minimize serious public health concerns for the next generation.