Article

The Diagnosis: Cutaneous Lymphoid Hyperplasia

Cutaneous lymphoid hyperplasia (CLH)(also known as pseudolymphoma or lymphocytoma cutis) is a benign inflammatory condition that typically presents as a flesh-colored to erythematous or violaceous papule or nodule on the head or neck. Cutaneous lymphoid hyperplasia may arise in response to an antigenic stimulus, such as an insect bite, infectious agent (eg, Borrelia species), medication, or foreign body (eg, tattoos and piercings).^1,2 Given the benign nature and potential for spontaneous resolution, treatment is conservative; however, high-potency topical steroids, cryosurgery, surgical excision, or local radiotherapy may lead to improvement.³ Our patient was started on clobetasol ointment 0.05% and topical tacrolimus 0.1%. After 3 months of use, she reported lesion improvement, but a new lesion appeared on the nose superior to the original. She was offered a steroid injection and liquid nitrogen freezing but was lost to follow-up.

The histopathologic features of CLH are variable and can resemble a cutaneous B- or T-cell lymphoma (quiz images). If there is B-cell predominance, histopathology typically shows a dense dermal infiltrate of lymphocytes admixed with sparse histiocytes, eosinophils, and plasma cells. Multiple germinal-center phenotype lymphoid follicles also may be seen.⁴ Histopathology of T-cell–predominant CLH commonly shows CD4⁺ T helper lymphocytes admixed with CD8⁺ T cells within the dermis with possible papillary dermal edema and red cell extravasation.⁵ Immunohistochemical stains for CD3, CD4, CD8, and CD20 usually are positive. Most lymphocytes are CD3⁺ T cells. Admixed clusters of CD20⁺ B cells may be present.

Angiolymphoid hyperplasia with eosinophilia is a vascular tumor of the skin composed of endothelial cells and inflammatory cells.^6,7 The condition presents as single or multiple flesh-colored to purple papules most commonly on the face, scalp, and ears.⁸ Histologically, lesions appear as well-circumscribed collections of blood vessels composed of plump endothelial cells and an inflammatory infiltrate with lymphocytes and eosinophils (Figure 1A). Endothelial cells also may have an epithelioid appearance.⁷ Apparent fenestrations—holes within endothelial cells—may be present (Figure 1B). Surgical excision is the preferred treatment of angiolymphoid hyperplasia with eosinophilia. Success with laser and cryosurgery also has been reported.

Granuloma faciale typically presents as a solitary redbrown papule or plaque on the face. Linear arborizing vessels and dilated follicular openings with brown globules frequently are seen on dermoscopy.⁹ Although it may resemble CLH clinically, the histopathology of granuloma faciale is characterized by a perivascular and interstitial dermal infiltrate of numerous eosinophils admixed with lymphocytes, plasma cells, and neutrophils underneath a grenz zone (Figure 2).¹⁰ Leukocytoclastic vasculitis may be seen in early lesions, and lesions can show variable angiocentric fibrosis.¹¹ Treatment options include intralesional triamcinolone, topical steroids or calcineurin inhibitors, topical psoralen plus UVA, surgical excision, and laser therapy, but outcomes are variable.¹²

Leukemia cutis is a malignant hematopoietic skin infiltration that presents as multiple pink to red-brown, firm, hemorrhagic papules most frequently involving the head, neck, and trunk.¹³ Rarely, lesions of leukemia cutis may present as ulcers or bullae. Most lesions occur at presentation of systemic leukemia or in the setting of established leukemia. The cutaneous involvement portends a poor prognosis, strongly correlating with additional extramedullary leukemic involvement.¹⁴ Histologic features vary based on the specific type of leukemia (eg, acute myelogenous leukemia). Generally, neoplastic infiltration of the dermis and subcutaneous tissue in a nodular, diffuse, perivascular, or interstitial pattern is seen (Figure 3).¹⁵ Leukemia cutis typically resolves after successful treatment of the underlying leukemia.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. In its early stages, MF presents as erythematous, brown, scaly patches and plaques. With progression to the tumor stage of disease, clonal expansion of CD4⁺ T cells leads to the development of purple papules and nodules.¹⁶ Microscopic findings of MF are dependent on the stage of disease. Early patch lesions show superficial or lichenoid lymphocytic infiltration of the epidermal basal layer.¹⁷ In the plaque stage, dermal infiltrates and epidermotropism become more pronounced, with increased atypical lymphocytes with cerebriform nuclei and interspersed inflammatory cells (Figure 4). In the tumor stage, lymphocytic infiltrates may involve the entirety of the dermis or extend into the subcutaneous tissue, and malignant cells become larger in size.¹⁷ Mycosis fungoides lesions typically stain positive for helper T-cell markers with a minority staining positive for CD8.

The Diagnosis: Cutaneous Lymphoid Hyperplasia

Cutaneous lymphoid hyperplasia (CLH)(also known as pseudolymphoma or lymphocytoma cutis) is a benign inflammatory condition that typically presents as a flesh-colored to erythematous or violaceous papule or nodule on the head or neck. Cutaneous lymphoid hyperplasia may arise in response to an antigenic stimulus, such as an insect bite, infectious agent (eg, Borrelia species), medication, or foreign body (eg, tattoos and piercings).^1,2 Given the benign nature and potential for spontaneous resolution, treatment is conservative; however, high-potency topical steroids, cryosurgery, surgical excision, or local radiotherapy may lead to improvement.³ Our patient was started on clobetasol ointment 0.05% and topical tacrolimus 0.1%. After 3 months of use, she reported lesion improvement, but a new lesion appeared on the nose superior to the original. She was offered a steroid injection and liquid nitrogen freezing but was lost to follow-up.

The histopathologic features of CLH are variable and can resemble a cutaneous B- or T-cell lymphoma (quiz images). If there is B-cell predominance, histopathology typically shows a dense dermal infiltrate of lymphocytes admixed with sparse histiocytes, eosinophils, and plasma cells. Multiple germinal-center phenotype lymphoid follicles also may be seen.⁴ Histopathology of T-cell–predominant CLH commonly shows CD4⁺ T helper lymphocytes admixed with CD8⁺ T cells within the dermis with possible papillary dermal edema and red cell extravasation.⁵ Immunohistochemical stains for CD3, CD4, CD8, and CD20 usually are positive. Most lymphocytes are CD3⁺ T cells. Admixed clusters of CD20⁺ B cells may be present.

Angiolymphoid hyperplasia with eosinophilia is a vascular tumor of the skin composed of endothelial cells and inflammatory cells.^6,7 The condition presents as single or multiple flesh-colored to purple papules most commonly on the face, scalp, and ears.⁸ Histologically, lesions appear as well-circumscribed collections of blood vessels composed of plump endothelial cells and an inflammatory infiltrate with lymphocytes and eosinophils (Figure 1A). Endothelial cells also may have an epithelioid appearance.⁷ Apparent fenestrations—holes within endothelial cells—may be present (Figure 1B). Surgical excision is the preferred treatment of angiolymphoid hyperplasia with eosinophilia. Success with laser and cryosurgery also has been reported.

Granuloma faciale typically presents as a solitary redbrown papule or plaque on the face. Linear arborizing vessels and dilated follicular openings with brown globules frequently are seen on dermoscopy.⁹ Although it may resemble CLH clinically, the histopathology of granuloma faciale is characterized by a perivascular and interstitial dermal infiltrate of numerous eosinophils admixed with lymphocytes, plasma cells, and neutrophils underneath a grenz zone (Figure 2).¹⁰ Leukocytoclastic vasculitis may be seen in early lesions, and lesions can show variable angiocentric fibrosis.¹¹ Treatment options include intralesional triamcinolone, topical steroids or calcineurin inhibitors, topical psoralen plus UVA, surgical excision, and laser therapy, but outcomes are variable.¹²

Leukemia cutis is a malignant hematopoietic skin infiltration that presents as multiple pink to red-brown, firm, hemorrhagic papules most frequently involving the head, neck, and trunk.¹³ Rarely, lesions of leukemia cutis may present as ulcers or bullae. Most lesions occur at presentation of systemic leukemia or in the setting of established leukemia. The cutaneous involvement portends a poor prognosis, strongly correlating with additional extramedullary leukemic involvement.¹⁴ Histologic features vary based on the specific type of leukemia (eg, acute myelogenous leukemia). Generally, neoplastic infiltration of the dermis and subcutaneous tissue in a nodular, diffuse, perivascular, or interstitial pattern is seen (Figure 3).¹⁵ Leukemia cutis typically resolves after successful treatment of the underlying leukemia.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. In its early stages, MF presents as erythematous, brown, scaly patches and plaques. With progression to the tumor stage of disease, clonal expansion of CD4⁺ T cells leads to the development of purple papules and nodules.¹⁶ Microscopic findings of MF are dependent on the stage of disease. Early patch lesions show superficial or lichenoid lymphocytic infiltration of the epidermal basal layer.¹⁷ In the plaque stage, dermal infiltrates and epidermotropism become more pronounced, with increased atypical lymphocytes with cerebriform nuclei and interspersed inflammatory cells (Figure 4). In the tumor stage, lymphocytic infiltrates may involve the entirety of the dermis or extend into the subcutaneous tissue, and malignant cells become larger in size.¹⁷ Mycosis fungoides lesions typically stain positive for helper T-cell markers with a minority staining positive for CD8.

The Diagnosis: Cutaneous Lymphoid Hyperplasia

Cutaneous lymphoid hyperplasia (CLH)(also known as pseudolymphoma or lymphocytoma cutis) is a benign inflammatory condition that typically presents as a flesh-colored to erythematous or violaceous papule or nodule on the head or neck. Cutaneous lymphoid hyperplasia may arise in response to an antigenic stimulus, such as an insect bite, infectious agent (eg, Borrelia species), medication, or foreign body (eg, tattoos and piercings).^1,2 Given the benign nature and potential for spontaneous resolution, treatment is conservative; however, high-potency topical steroids, cryosurgery, surgical excision, or local radiotherapy may lead to improvement.³ Our patient was started on clobetasol ointment 0.05% and topical tacrolimus 0.1%. After 3 months of use, she reported lesion improvement, but a new lesion appeared on the nose superior to the original. She was offered a steroid injection and liquid nitrogen freezing but was lost to follow-up.

The histopathologic features of CLH are variable and can resemble a cutaneous B- or T-cell lymphoma (quiz images). If there is B-cell predominance, histopathology typically shows a dense dermal infiltrate of lymphocytes admixed with sparse histiocytes, eosinophils, and plasma cells. Multiple germinal-center phenotype lymphoid follicles also may be seen.⁴ Histopathology of T-cell–predominant CLH commonly shows CD4⁺ T helper lymphocytes admixed with CD8⁺ T cells within the dermis with possible papillary dermal edema and red cell extravasation.⁵ Immunohistochemical stains for CD3, CD4, CD8, and CD20 usually are positive. Most lymphocytes are CD3⁺ T cells. Admixed clusters of CD20⁺ B cells may be present.

Angiolymphoid hyperplasia with eosinophilia is a vascular tumor of the skin composed of endothelial cells and inflammatory cells.^6,7 The condition presents as single or multiple flesh-colored to purple papules most commonly on the face, scalp, and ears.⁸ Histologically, lesions appear as well-circumscribed collections of blood vessels composed of plump endothelial cells and an inflammatory infiltrate with lymphocytes and eosinophils (Figure 1A). Endothelial cells also may have an epithelioid appearance.⁷ Apparent fenestrations—holes within endothelial cells—may be present (Figure 1B). Surgical excision is the preferred treatment of angiolymphoid hyperplasia with eosinophilia. Success with laser and cryosurgery also has been reported.

Granuloma faciale typically presents as a solitary redbrown papule or plaque on the face. Linear arborizing vessels and dilated follicular openings with brown globules frequently are seen on dermoscopy.⁹ Although it may resemble CLH clinically, the histopathology of granuloma faciale is characterized by a perivascular and interstitial dermal infiltrate of numerous eosinophils admixed with lymphocytes, plasma cells, and neutrophils underneath a grenz zone (Figure 2).¹⁰ Leukocytoclastic vasculitis may be seen in early lesions, and lesions can show variable angiocentric fibrosis.¹¹ Treatment options include intralesional triamcinolone, topical steroids or calcineurin inhibitors, topical psoralen plus UVA, surgical excision, and laser therapy, but outcomes are variable.¹²

Leukemia cutis is a malignant hematopoietic skin infiltration that presents as multiple pink to red-brown, firm, hemorrhagic papules most frequently involving the head, neck, and trunk.¹³ Rarely, lesions of leukemia cutis may present as ulcers or bullae. Most lesions occur at presentation of systemic leukemia or in the setting of established leukemia. The cutaneous involvement portends a poor prognosis, strongly correlating with additional extramedullary leukemic involvement.¹⁴ Histologic features vary based on the specific type of leukemia (eg, acute myelogenous leukemia). Generally, neoplastic infiltration of the dermis and subcutaneous tissue in a nodular, diffuse, perivascular, or interstitial pattern is seen (Figure 3).¹⁵ Leukemia cutis typically resolves after successful treatment of the underlying leukemia.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. In its early stages, MF presents as erythematous, brown, scaly patches and plaques. With progression to the tumor stage of disease, clonal expansion of CD4⁺ T cells leads to the development of purple papules and nodules.¹⁶ Microscopic findings of MF are dependent on the stage of disease. Early patch lesions show superficial or lichenoid lymphocytic infiltration of the epidermal basal layer.¹⁷ In the plaque stage, dermal infiltrates and epidermotropism become more pronounced, with increased atypical lymphocytes with cerebriform nuclei and interspersed inflammatory cells (Figure 4). In the tumor stage, lymphocytic infiltrates may involve the entirety of the dermis or extend into the subcutaneous tissue, and malignant cells become larger in size.¹⁷ Mycosis fungoides lesions typically stain positive for helper T-cell markers with a minority staining positive for CD8.

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are 2 common inflammatory skin conditions that may have similar clinical presentations. Historically, it was thought that these conditions could not be diagnosed simultaneously due to their differing immune mechanisms; however, this belief has been challenged by recent evidence suggesting a more nuanced relationship between the 2 disease processes. In this review, we examine the complex interplay between AD and ACD and explain how shifts in conventional understanding of the 2 conditions shaped our evolving recognition of their ability to coexist.

Epidemiology of AD and ACD

Atopic dermatitis is the most common inflammatory skin disease in children and adolescents, with an estimated prevalence reaching 21%.¹ In 60% of cases, onset of AD will occur within the first year of life, and 90% of cases begin within the first 5 years.² Resolution may occur by adulthood; however, AD may continue to impact up to 8% to 9% of adults, with an increased prevalence in those older than 75 years.¹ This may represent an underestimation of the burden of adult AD; one systematic review of 17 studies found that the pooled proportion of adult-onset AD was greater than 25%.³

In contrast, ACD previously was assumed to be a disease that more commonly impacted adults and only rarely children, primarily due to an early misconception that children were not frequently exposed to contact allergens and their immune systems were too immature to react to them even if exposed.^4,5 However, it is now known that children do have risk factors for development of ACD, including a thinner stratum corneum and potentially a more absorbent skin surface.⁴ In addition, a 2022 study by the North American Contact Dermatitis Group (NACDG) found similar rates of ACD in children (n=1871) and adults (n=41,699) referred for patch testing (55.2% and 57.3%, respectively) as well as similar rates of having at least 1 relevant positive patch test (49.2% and 52.2%).⁶

In opposition to traditional beliefs, these findings highlight that AD and ACD can occur across age groups.

Immune Mechanism

The pathogenesis of AD represents a multifactorial process involving the immune system, cutaneous flora, genetic predisposition, and surrounding environment. Immunologically, acute AD is driven by a predominantly T_H2 helper T-cell response with high levels of IL-4, IL-5, and IL-13⁷; T_H22, T_H17, and T_H1 also have been implicated.⁸ Notably, T_H17 is found in high levels during the acute eczema phase, while T_H1 and T_H22are associated with the chronic phase.⁷

The pathophysiology of ACD is not completely understood. The classic paradigm involves 2 phases: sensitization and elicitation. Sensitization involves antigen-presenting cells that take up allergens absorbed by the skin to present them in regional lymph nodes where antigen-specific T lymphocytes are generated. Elicitation occurs upon re-exposure to the allergen, at which time the primed T lymphocytes are recruited to the skin, causing inflammation.⁹ Allergic contact dermatitis initially was thought to be driven by T_H1 cytokines and IL-17 but now is understood to be more complex.¹⁰ Studies have revealed immune polarization of contact allergens, demonstrating that nickel primarily induces a T_H1/T_H17 response, whereas fragrance and rubber accelerators skew to T_H2; T_H9 and T_H22 also may be involved depending on the causative allergen.^11,12

Of note, the immunologic differences between AD and ACD led early investigators to believe that patients with AD were relatively protected from ACD.¹³ However, as previously described, there are several overlapping cytokines between AD and ACD. Furthermore, research has revealed that risk of contact sensitization might be increased in the chronic eczema phase due to the shared T_H1 pathway.¹⁴ Barrier-disrupted skin (such as that in AD) also may increase the cytokine response and the density of antigen-presenting cells, leading to a proallergic state.¹⁵ This suggests that the immunologic pathways of AD and ACD are more intertwined than was previously understood.

Underlying Risk Factors

Skin barrier dysfunction is a key step in the pathogenesis of AD. Patients with AD commonly have loss-of-function mutations in the filaggrin gene, a protein that is key to the function of the stratum corneum. Loss of this protein may not only impact the immune response as previously noted but also may lead to increased transepidermal water loss and bacterial colonization.¹⁶ Interestingly, a 2014 review examined how this mutation could lead to an increased risk of sensitization to bivalent metal ions via an impaired chelating ability of the skin.¹⁷ Furthermore, a 2016 study conducted in Dutch construction workers revealed an increased risk for contact dermatitis (irritant and allergic) for those with a loss-of-function filaggrin mutation.¹⁸

Importantly, this same mutation may explain why patients with AD tend to have increased skin colonization by Staphylococcus aureus. The abundance of S aureus and the relative decrease in the diversity of other microorganisms on the skin may be associated with increased AD severity.¹⁹ Likewise, S aureus may play a role in the pathogenesis of ACD via production of its exotoxin directed at the T-cell receptor V beta 17 region. In particular, this receptor has been associated with nickel sensitization.¹⁷

Another risk factor to consider is increased exposure to contact sensitizers when treating AD. For instance, management often includes use of over-the-counter emollients, natural or botanical remedies with purported benefits for AD, cleansers, and detergents. However, these products can contain some of the most prevalent contact allergens seen in those with AD, including methyl-isothiazolinone, formaldehyde releasers, and fragrance.²⁰ Topical corticosteroids also are frequently used, and ACD to steroid molecules can occur, particularly to tixocortol-21-pivalate (a marker for class A corticosteroids) and budesonide (a marker for class B corticosteroids).²¹ Other allergens (eg, benzyl alcohol, propylene glycol) also may be found as inactive ingredients of topical corticosteroids.²² These exposures may place AD patients at risk for ACD.

The Coexistence of AD and ACD

Given the overlapping epidemiology, immunology, and potentially increased risk for the development of ACD in patients with AD, it would be reasonable to assume that the 2 diagnoses could coexist; however, is there clinical data to support this idea? Based on recent database reviews, the answer appears to be yes.^20,23-26 An analysis from the Pediatric Contact Dermatitis Registry revealed that 30% of 1142 pediatric patch test cases analyzed were diagnosed as AD and ACD simultaneously.²⁴ The NACDG found similar results in its 2021 review, as 29.5% of children (n=1648) and 20.7% of adults (n=36,834) had a concurrent diagnosis of AD and ACD.²⁰ Notably, older results from these databases also demonstrated an association between the 2 conditions.^23,25,26

It remains unclear whether the prevalence of ACD is higher in those with or without AD. A comprehensive systematic review conducted in 2017 examined this topic through analysis of 74 studies. The results demonstrated a similar prevalence of contact sensitization in individuals with and without AD.²⁷ Another systematic review of 31 studies conducted in 2017 found a higher prevalence for ACD in children without AD; however, the authors noted that the included studies were too variable (eg, size, design, allergens tested) to draw definitive conclusions.²⁸

Even though there is no clear overall increased risk for ACD in patients with AD, research has suggested that certain allergens may be more prevalent in the setting of AD. An NACDG study found that adults with AD had increased odds of reacting to 10 of the top 25 NACDG screening allergens compared to those without AD.²⁰ Other studies have found that AD patients may be more likely to become sensitized to certain allergens, such as fragrance and lanolin.¹⁴

Considerations for Management

Diagnosis of ACD in patients with AD can be challenging because these conditions may present similarly with chronic, pruritic, inflammatory patches and plaques. Chronic ACD may be misdiagnosed as AD if patch testing is not performed.²⁹ Given the prevalence of ACD in the setting of AD, there should be a low threshold to pursue patch testing, especially when dermatitis is recalcitrant to standard therapies or presents in an atypical distribution (ie, perioral, predominantly head/neck, hand and foot, isolated eyelid involvement, buttocks).^4,30 Various allergen series are available for patch testing adults and children including the NACDG Standard Series, American Contact Dermatitis Society Core Allergen Series, or the Pediatric Baseline Series.^31-33

If potentially relevant allergens are uncovered by patch testing, patients should be counseled on avoidance strategies. However, allergen avoidance may not always lead to complete symptom resolution, especially if AD is present concomitantly with ACD. Therefore, use of topical or systemic therapies still may be required. Topical corticosteroids can be used when dermatitis is acute and localized. Systemic corticosteroids are utilized for both diagnoses when cases are more severe or extensive, but their adverse-effect profile limits long-term use. Other systemic treatments, including conventional agents (ie, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil), biologics, and small molecule inhibitors also may be considered for severe cases.^34,35 Dupilumab, a monoclonal antibody targeting IL-4/IL-13, is approved for use in moderate to severe AD in patients 6 months and older. Recent evidence has suggested that dupilumab also may be an effective off-label treatment choice for ACD when allergen avoidance alone is insufficient.³⁶ Studies have been conducted on secukinumab, a monoclonal antibody against IL-17; however, it has not been shown to be effective in either AD or ACD.^37,38 This indicates that targeted biologics may not always be successful in treating these diagnoses, likely due to their complex immune pathways. Finally, there is an emerging role for JAK inhibitors. Three are approved for AD: topical ruxolitinib, oral abrocitinib, and oral upadacitinib.³⁹ Further investigation is needed to determine the efficacy of JAK inhibitors in ACD.

Final Interpretation

Evolving evidence shows that AD and ACD can occur at the same time despite the historical perspective that their immune pathways were too polarized for this to happen. Atopic dermatitis may be an important risk factor for subsequent development of ACD. Management should include a low threshold to perform patch testing, while pharmacotherapies utilized in the treatment of both conditions should be considered.

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are 2 common inflammatory skin conditions that may have similar clinical presentations. Historically, it was thought that these conditions could not be diagnosed simultaneously due to their differing immune mechanisms; however, this belief has been challenged by recent evidence suggesting a more nuanced relationship between the 2 disease processes. In this review, we examine the complex interplay between AD and ACD and explain how shifts in conventional understanding of the 2 conditions shaped our evolving recognition of their ability to coexist.

Epidemiology of AD and ACD

Atopic dermatitis is the most common inflammatory skin disease in children and adolescents, with an estimated prevalence reaching 21%.¹ In 60% of cases, onset of AD will occur within the first year of life, and 90% of cases begin within the first 5 years.² Resolution may occur by adulthood; however, AD may continue to impact up to 8% to 9% of adults, with an increased prevalence in those older than 75 years.¹ This may represent an underestimation of the burden of adult AD; one systematic review of 17 studies found that the pooled proportion of adult-onset AD was greater than 25%.³

In contrast, ACD previously was assumed to be a disease that more commonly impacted adults and only rarely children, primarily due to an early misconception that children were not frequently exposed to contact allergens and their immune systems were too immature to react to them even if exposed.^4,5 However, it is now known that children do have risk factors for development of ACD, including a thinner stratum corneum and potentially a more absorbent skin surface.⁴ In addition, a 2022 study by the North American Contact Dermatitis Group (NACDG) found similar rates of ACD in children (n=1871) and adults (n=41,699) referred for patch testing (55.2% and 57.3%, respectively) as well as similar rates of having at least 1 relevant positive patch test (49.2% and 52.2%).⁶

In opposition to traditional beliefs, these findings highlight that AD and ACD can occur across age groups.

Immune Mechanism

The pathogenesis of AD represents a multifactorial process involving the immune system, cutaneous flora, genetic predisposition, and surrounding environment. Immunologically, acute AD is driven by a predominantly T_H2 helper T-cell response with high levels of IL-4, IL-5, and IL-13⁷; T_H22, T_H17, and T_H1 also have been implicated.⁸ Notably, T_H17 is found in high levels during the acute eczema phase, while T_H1 and T_H22are associated with the chronic phase.⁷

The pathophysiology of ACD is not completely understood. The classic paradigm involves 2 phases: sensitization and elicitation. Sensitization involves antigen-presenting cells that take up allergens absorbed by the skin to present them in regional lymph nodes where antigen-specific T lymphocytes are generated. Elicitation occurs upon re-exposure to the allergen, at which time the primed T lymphocytes are recruited to the skin, causing inflammation.⁹ Allergic contact dermatitis initially was thought to be driven by T_H1 cytokines and IL-17 but now is understood to be more complex.¹⁰ Studies have revealed immune polarization of contact allergens, demonstrating that nickel primarily induces a T_H1/T_H17 response, whereas fragrance and rubber accelerators skew to T_H2; T_H9 and T_H22 also may be involved depending on the causative allergen.^11,12

Of note, the immunologic differences between AD and ACD led early investigators to believe that patients with AD were relatively protected from ACD.¹³ However, as previously described, there are several overlapping cytokines between AD and ACD. Furthermore, research has revealed that risk of contact sensitization might be increased in the chronic eczema phase due to the shared T_H1 pathway.¹⁴ Barrier-disrupted skin (such as that in AD) also may increase the cytokine response and the density of antigen-presenting cells, leading to a proallergic state.¹⁵ This suggests that the immunologic pathways of AD and ACD are more intertwined than was previously understood.

Underlying Risk Factors

Skin barrier dysfunction is a key step in the pathogenesis of AD. Patients with AD commonly have loss-of-function mutations in the filaggrin gene, a protein that is key to the function of the stratum corneum. Loss of this protein may not only impact the immune response as previously noted but also may lead to increased transepidermal water loss and bacterial colonization.¹⁶ Interestingly, a 2014 review examined how this mutation could lead to an increased risk of sensitization to bivalent metal ions via an impaired chelating ability of the skin.¹⁷ Furthermore, a 2016 study conducted in Dutch construction workers revealed an increased risk for contact dermatitis (irritant and allergic) for those with a loss-of-function filaggrin mutation.¹⁸

Importantly, this same mutation may explain why patients with AD tend to have increased skin colonization by Staphylococcus aureus. The abundance of S aureus and the relative decrease in the diversity of other microorganisms on the skin may be associated with increased AD severity.¹⁹ Likewise, S aureus may play a role in the pathogenesis of ACD via production of its exotoxin directed at the T-cell receptor V beta 17 region. In particular, this receptor has been associated with nickel sensitization.¹⁷

Another risk factor to consider is increased exposure to contact sensitizers when treating AD. For instance, management often includes use of over-the-counter emollients, natural or botanical remedies with purported benefits for AD, cleansers, and detergents. However, these products can contain some of the most prevalent contact allergens seen in those with AD, including methyl-isothiazolinone, formaldehyde releasers, and fragrance.²⁰ Topical corticosteroids also are frequently used, and ACD to steroid molecules can occur, particularly to tixocortol-21-pivalate (a marker for class A corticosteroids) and budesonide (a marker for class B corticosteroids).²¹ Other allergens (eg, benzyl alcohol, propylene glycol) also may be found as inactive ingredients of topical corticosteroids.²² These exposures may place AD patients at risk for ACD.

The Coexistence of AD and ACD

Given the overlapping epidemiology, immunology, and potentially increased risk for the development of ACD in patients with AD, it would be reasonable to assume that the 2 diagnoses could coexist; however, is there clinical data to support this idea? Based on recent database reviews, the answer appears to be yes.^20,23-26 An analysis from the Pediatric Contact Dermatitis Registry revealed that 30% of 1142 pediatric patch test cases analyzed were diagnosed as AD and ACD simultaneously.²⁴ The NACDG found similar results in its 2021 review, as 29.5% of children (n=1648) and 20.7% of adults (n=36,834) had a concurrent diagnosis of AD and ACD.²⁰ Notably, older results from these databases also demonstrated an association between the 2 conditions.^23,25,26

It remains unclear whether the prevalence of ACD is higher in those with or without AD. A comprehensive systematic review conducted in 2017 examined this topic through analysis of 74 studies. The results demonstrated a similar prevalence of contact sensitization in individuals with and without AD.²⁷ Another systematic review of 31 studies conducted in 2017 found a higher prevalence for ACD in children without AD; however, the authors noted that the included studies were too variable (eg, size, design, allergens tested) to draw definitive conclusions.²⁸

Even though there is no clear overall increased risk for ACD in patients with AD, research has suggested that certain allergens may be more prevalent in the setting of AD. An NACDG study found that adults with AD had increased odds of reacting to 10 of the top 25 NACDG screening allergens compared to those without AD.²⁰ Other studies have found that AD patients may be more likely to become sensitized to certain allergens, such as fragrance and lanolin.¹⁴

Considerations for Management

Diagnosis of ACD in patients with AD can be challenging because these conditions may present similarly with chronic, pruritic, inflammatory patches and plaques. Chronic ACD may be misdiagnosed as AD if patch testing is not performed.²⁹ Given the prevalence of ACD in the setting of AD, there should be a low threshold to pursue patch testing, especially when dermatitis is recalcitrant to standard therapies or presents in an atypical distribution (ie, perioral, predominantly head/neck, hand and foot, isolated eyelid involvement, buttocks).^4,30 Various allergen series are available for patch testing adults and children including the NACDG Standard Series, American Contact Dermatitis Society Core Allergen Series, or the Pediatric Baseline Series.^31-33

If potentially relevant allergens are uncovered by patch testing, patients should be counseled on avoidance strategies. However, allergen avoidance may not always lead to complete symptom resolution, especially if AD is present concomitantly with ACD. Therefore, use of topical or systemic therapies still may be required. Topical corticosteroids can be used when dermatitis is acute and localized. Systemic corticosteroids are utilized for both diagnoses when cases are more severe or extensive, but their adverse-effect profile limits long-term use. Other systemic treatments, including conventional agents (ie, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil), biologics, and small molecule inhibitors also may be considered for severe cases.^34,35 Dupilumab, a monoclonal antibody targeting IL-4/IL-13, is approved for use in moderate to severe AD in patients 6 months and older. Recent evidence has suggested that dupilumab also may be an effective off-label treatment choice for ACD when allergen avoidance alone is insufficient.³⁶ Studies have been conducted on secukinumab, a monoclonal antibody against IL-17; however, it has not been shown to be effective in either AD or ACD.^37,38 This indicates that targeted biologics may not always be successful in treating these diagnoses, likely due to their complex immune pathways. Finally, there is an emerging role for JAK inhibitors. Three are approved for AD: topical ruxolitinib, oral abrocitinib, and oral upadacitinib.³⁹ Further investigation is needed to determine the efficacy of JAK inhibitors in ACD.

Final Interpretation

Evolving evidence shows that AD and ACD can occur at the same time despite the historical perspective that their immune pathways were too polarized for this to happen. Atopic dermatitis may be an important risk factor for subsequent development of ACD. Management should include a low threshold to perform patch testing, while pharmacotherapies utilized in the treatment of both conditions should be considered.

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are 2 common inflammatory skin conditions that may have similar clinical presentations. Historically, it was thought that these conditions could not be diagnosed simultaneously due to their differing immune mechanisms; however, this belief has been challenged by recent evidence suggesting a more nuanced relationship between the 2 disease processes. In this review, we examine the complex interplay between AD and ACD and explain how shifts in conventional understanding of the 2 conditions shaped our evolving recognition of their ability to coexist.

Epidemiology of AD and ACD

Atopic dermatitis is the most common inflammatory skin disease in children and adolescents, with an estimated prevalence reaching 21%.¹ In 60% of cases, onset of AD will occur within the first year of life, and 90% of cases begin within the first 5 years.² Resolution may occur by adulthood; however, AD may continue to impact up to 8% to 9% of adults, with an increased prevalence in those older than 75 years.¹ This may represent an underestimation of the burden of adult AD; one systematic review of 17 studies found that the pooled proportion of adult-onset AD was greater than 25%.³

In contrast, ACD previously was assumed to be a disease that more commonly impacted adults and only rarely children, primarily due to an early misconception that children were not frequently exposed to contact allergens and their immune systems were too immature to react to them even if exposed.^4,5 However, it is now known that children do have risk factors for development of ACD, including a thinner stratum corneum and potentially a more absorbent skin surface.⁴ In addition, a 2022 study by the North American Contact Dermatitis Group (NACDG) found similar rates of ACD in children (n=1871) and adults (n=41,699) referred for patch testing (55.2% and 57.3%, respectively) as well as similar rates of having at least 1 relevant positive patch test (49.2% and 52.2%).⁶

In opposition to traditional beliefs, these findings highlight that AD and ACD can occur across age groups.

Immune Mechanism

The pathogenesis of AD represents a multifactorial process involving the immune system, cutaneous flora, genetic predisposition, and surrounding environment. Immunologically, acute AD is driven by a predominantly T_H2 helper T-cell response with high levels of IL-4, IL-5, and IL-13⁷; T_H22, T_H17, and T_H1 also have been implicated.⁸ Notably, T_H17 is found in high levels during the acute eczema phase, while T_H1 and T_H22are associated with the chronic phase.⁷

The pathophysiology of ACD is not completely understood. The classic paradigm involves 2 phases: sensitization and elicitation. Sensitization involves antigen-presenting cells that take up allergens absorbed by the skin to present them in regional lymph nodes where antigen-specific T lymphocytes are generated. Elicitation occurs upon re-exposure to the allergen, at which time the primed T lymphocytes are recruited to the skin, causing inflammation.⁹ Allergic contact dermatitis initially was thought to be driven by T_H1 cytokines and IL-17 but now is understood to be more complex.¹⁰ Studies have revealed immune polarization of contact allergens, demonstrating that nickel primarily induces a T_H1/T_H17 response, whereas fragrance and rubber accelerators skew to T_H2; T_H9 and T_H22 also may be involved depending on the causative allergen.^11,12

Of note, the immunologic differences between AD and ACD led early investigators to believe that patients with AD were relatively protected from ACD.¹³ However, as previously described, there are several overlapping cytokines between AD and ACD. Furthermore, research has revealed that risk of contact sensitization might be increased in the chronic eczema phase due to the shared T_H1 pathway.¹⁴ Barrier-disrupted skin (such as that in AD) also may increase the cytokine response and the density of antigen-presenting cells, leading to a proallergic state.¹⁵ This suggests that the immunologic pathways of AD and ACD are more intertwined than was previously understood.

Underlying Risk Factors

Skin barrier dysfunction is a key step in the pathogenesis of AD. Patients with AD commonly have loss-of-function mutations in the filaggrin gene, a protein that is key to the function of the stratum corneum. Loss of this protein may not only impact the immune response as previously noted but also may lead to increased transepidermal water loss and bacterial colonization.¹⁶ Interestingly, a 2014 review examined how this mutation could lead to an increased risk of sensitization to bivalent metal ions via an impaired chelating ability of the skin.¹⁷ Furthermore, a 2016 study conducted in Dutch construction workers revealed an increased risk for contact dermatitis (irritant and allergic) for those with a loss-of-function filaggrin mutation.¹⁸

Importantly, this same mutation may explain why patients with AD tend to have increased skin colonization by Staphylococcus aureus. The abundance of S aureus and the relative decrease in the diversity of other microorganisms on the skin may be associated with increased AD severity.¹⁹ Likewise, S aureus may play a role in the pathogenesis of ACD via production of its exotoxin directed at the T-cell receptor V beta 17 region. In particular, this receptor has been associated with nickel sensitization.¹⁷

Another risk factor to consider is increased exposure to contact sensitizers when treating AD. For instance, management often includes use of over-the-counter emollients, natural or botanical remedies with purported benefits for AD, cleansers, and detergents. However, these products can contain some of the most prevalent contact allergens seen in those with AD, including methyl-isothiazolinone, formaldehyde releasers, and fragrance.²⁰ Topical corticosteroids also are frequently used, and ACD to steroid molecules can occur, particularly to tixocortol-21-pivalate (a marker for class A corticosteroids) and budesonide (a marker for class B corticosteroids).²¹ Other allergens (eg, benzyl alcohol, propylene glycol) also may be found as inactive ingredients of topical corticosteroids.²² These exposures may place AD patients at risk for ACD.

The Coexistence of AD and ACD

Given the overlapping epidemiology, immunology, and potentially increased risk for the development of ACD in patients with AD, it would be reasonable to assume that the 2 diagnoses could coexist; however, is there clinical data to support this idea? Based on recent database reviews, the answer appears to be yes.^20,23-26 An analysis from the Pediatric Contact Dermatitis Registry revealed that 30% of 1142 pediatric patch test cases analyzed were diagnosed as AD and ACD simultaneously.²⁴ The NACDG found similar results in its 2021 review, as 29.5% of children (n=1648) and 20.7% of adults (n=36,834) had a concurrent diagnosis of AD and ACD.²⁰ Notably, older results from these databases also demonstrated an association between the 2 conditions.^23,25,26

It remains unclear whether the prevalence of ACD is higher in those with or without AD. A comprehensive systematic review conducted in 2017 examined this topic through analysis of 74 studies. The results demonstrated a similar prevalence of contact sensitization in individuals with and without AD.²⁷ Another systematic review of 31 studies conducted in 2017 found a higher prevalence for ACD in children without AD; however, the authors noted that the included studies were too variable (eg, size, design, allergens tested) to draw definitive conclusions.²⁸

Even though there is no clear overall increased risk for ACD in patients with AD, research has suggested that certain allergens may be more prevalent in the setting of AD. An NACDG study found that adults with AD had increased odds of reacting to 10 of the top 25 NACDG screening allergens compared to those without AD.²⁰ Other studies have found that AD patients may be more likely to become sensitized to certain allergens, such as fragrance and lanolin.¹⁴

Considerations for Management

Diagnosis of ACD in patients with AD can be challenging because these conditions may present similarly with chronic, pruritic, inflammatory patches and plaques. Chronic ACD may be misdiagnosed as AD if patch testing is not performed.²⁹ Given the prevalence of ACD in the setting of AD, there should be a low threshold to pursue patch testing, especially when dermatitis is recalcitrant to standard therapies or presents in an atypical distribution (ie, perioral, predominantly head/neck, hand and foot, isolated eyelid involvement, buttocks).^4,30 Various allergen series are available for patch testing adults and children including the NACDG Standard Series, American Contact Dermatitis Society Core Allergen Series, or the Pediatric Baseline Series.^31-33

If potentially relevant allergens are uncovered by patch testing, patients should be counseled on avoidance strategies. However, allergen avoidance may not always lead to complete symptom resolution, especially if AD is present concomitantly with ACD. Therefore, use of topical or systemic therapies still may be required. Topical corticosteroids can be used when dermatitis is acute and localized. Systemic corticosteroids are utilized for both diagnoses when cases are more severe or extensive, but their adverse-effect profile limits long-term use. Other systemic treatments, including conventional agents (ie, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil), biologics, and small molecule inhibitors also may be considered for severe cases.^34,35 Dupilumab, a monoclonal antibody targeting IL-4/IL-13, is approved for use in moderate to severe AD in patients 6 months and older. Recent evidence has suggested that dupilumab also may be an effective off-label treatment choice for ACD when allergen avoidance alone is insufficient.³⁶ Studies have been conducted on secukinumab, a monoclonal antibody against IL-17; however, it has not been shown to be effective in either AD or ACD.^37,38 This indicates that targeted biologics may not always be successful in treating these diagnoses, likely due to their complex immune pathways. Finally, there is an emerging role for JAK inhibitors. Three are approved for AD: topical ruxolitinib, oral abrocitinib, and oral upadacitinib.³⁹ Further investigation is needed to determine the efficacy of JAK inhibitors in ACD.

Final Interpretation

Evolving evidence shows that AD and ACD can occur at the same time despite the historical perspective that their immune pathways were too polarized for this to happen. Atopic dermatitis may be an important risk factor for subsequent development of ACD. Management should include a low threshold to perform patch testing, while pharmacotherapies utilized in the treatment of both conditions should be considered.

Basal cell carcinomas (BCCs) are considered the most common cutaneous cancers. Approximately 80% of nonmelanoma skin cancers are BCCs.^1,2 Surgical management is the gold standard for early-stage and localized BCCs; it may include simple excision vs Mohs micrographic surgery.^3,4 However, if left untreated, these lesions can progress to an advanced stage (locally advanced BCC) or infrequently may spread to distant sites (metastatic BCC). In the advanced stage, the lesions are no longer manageable by surgery or radiation therapy.^5,6 Recently, inhibitors targeting the hedgehog (Hh) pathway have shown great promise for these patients. The first drug approved by the US Food and Drug Administration (FDA) for locally advanced and metastatic BCC is vismodegib.⁷ In this article, we provide a clinical review of vismodegib for the management of BCC, including a discussion of the Hh pathway in BCC, adverse effects of vismodegib, use of vismodegib in adnexal skin tumors, recommended doses for vismodegib therapy in BCC, and management of the side effects of treatment.

Hh Pathway in BCC

In embryonic development, the Hh signaling pathway is crucial across a broad spectrum of species, including humans. Various members of the Hh family have been recognized, all working as secreted regulatory proteins.⁸ The name of the Hh signaling pathway is derived from a polypeptide ligand called hedgehog found in some fruit flies. Mutations in the gene led to fruit fly larvae that had a spiky hairy pattern of denticles similar to hedgehogs, leading to the name of this molecule.⁹ The transmembrane protein smoothened (SMO) is the main component of the Hh signaling pathway and initiates a signaling cascade that in turn leads to an increased expression of target genes, such as GLI1. Patched (PTCH), also a transmembrane protein and a cell-surface receptor for the secreted Hh ligand, suppresses the signaling capacity of SMO. Upon binding of the Hh ligand to the PTCH receptor, the suppression of SMO is relieved and a signal is propagated, evoking a cellular response.¹⁰ Molecular and genetic studies have reported that genetic alterations in the Hh signaling pathway are almost universally present in all BCCs, leading to an aberrant activation of the pathway and an uncontrolled proliferation of the basal cells. Frequently, these alterations have been shown to cause loss of function of PTCH homologue 1, which usually acts to inhibit the SMO homologue signaling activity.^11,12

Because of the potential importance of Hh signaling in other solid malignancies and the failure of topical inhibition of SMO,¹³ subsequent studies on the development of Hh pathway inhibitors have mostly focused on the systemic approach. A multitude of Hh pathway inhibitors have been developed thus far, such as SANT1-SANT4, GDC-0449, IPI-926, BMS-833923 (XL139), HhAntag-691, and MK-4101.¹⁴ Many of these inhibitors have been clinically investigated.^13,15,16

Systemic SMO Inhibitor: Vismodegib

Vismodegib was the earliest systemic SMO inhibitor to fulfill early clinical evaluation^15,16 and the first drug to receive FDA approval for the management of advanced or metastatic BCC. Vismodegib is a small-molecule SMO inhibitor used for the management of selected locally advanced BCC and metastatic BCC in adults.^3,17 Although there is a possibility of recurrence following drug withdrawal, vismodegib constitutes a new therapeutic strategy presenting positive benefits to patients. It may provide superior improvement over sunitinib, which has shown efficacy in a few patients; however, the efficacy and tolerance of sunitinib have been shown to be limited.^18,19

Adverse Effects of Vismodegib Therapy

Adverse events with vismodegib use have been reported in 98% of patients (N=491); most of these were mild to moderate.²⁰ However, the frequency of adverse events could prove to be a therapeutic challenge for patients requiring extended treatment. The most frequently reported reversible side effects were muscle spasms (64%), alopecia (62%), weight loss (33%), fatigue (28%), decreased appetite (25%), diarrhea (17%), nausea (16%), dysgeusia (54%), and ageusia (22%).²⁰ In clinical trials, amenorrhea was noticed in 30% (3/10) of females with reproductive potential.² Apart from alopecia and possibly amenorrhea, these side effects are reversible.¹⁷ Alkeraye et al¹⁷ reported 3 clinical cases of persistent alopecia following the use of vismodegib. Amenorrhea is a possible side effect of unknown reversibility.⁷

Vismodegib is a pregnancy category D medication.⁴ Severe birth defects, including craniofacial abnormalities, retardations in normal growth, open perineum, and absence of digital fusion at a corresponding 20% of the recommended daily dose, were found in rat studies. Embryo-fetal death was noted when rats were exposedto concentrations comparable to the recommended human dose.⁴

Hepatic events with the use of vismodegib have been reported. The use of vismodegib in randomized controlled trials resulted in elevation of both alanine aminotransferase and aspartate aminotransferase levels compared with placebo.²¹ Moreover, severe hepatotoxicity with vismodegib has been reported.^22-24 A study conducted by Edwards et al²⁵ concluded that the use of vismodegib in patients with severe liver disease must include thorough risk-benefit assessment, with caution in using other concomitant hepatotoxic medications.

Rare adverse events also have been reported in the literature, including vismodegib-induced pancreatitis in a 79-year-old patient treated for locally advanced, recurrent BCC that was cleared following cessation of therapy.²⁶ Additionally, atypical fibroxanthoma was observed in an 83-year-old patient after 30 days of treatment with vismodegib for multiple BCCs.²⁷ The development of other secondary malignancies, such as squamous cell carcinoma, melanoma, keratoacanthomas, and pilomatricomas, during or after the long-term use of vismodegib also have been described.^28-35

Use of Vismodegib for Adnexal Skin Tumors

The role of the sonic Hh–PTCH pathway in the pathogenesis of adnexal tumors varies in the literature. Some studies propose the involvement of this pathway in the formation of adnexal tumors such as trichoblastoma, trichoepithelioma, and cylindroma, as in BCC. Various lines of evidence support this involvement. Firstly, in mice, the spontaneous generation of numerous BCCs, trichoblastomas, trichoepitheliomas, and cylindromas has been observed following constitutive activation of the sonic Hh–PTCH pathway.³⁶ Secondly, in trichoepitheliomas, there have been positive results in molecular research into the tumor suppressor gene PTCH homologue 1, PTCH1, whose mutations cause constitutive activation of the sonic Hh–PTCH pathway.³⁷ Thirdly, GLI1³⁸ and SOX9³⁹ transcription factors associated with the signaling pathway of sonic Hh–PTCH appear to have increased levels in adnexal carcinomas.¹⁹ Lepesant et al¹⁹ reported a notable clinical response to vismodegib in trichoblastic carcinoma. Baur et al⁴⁰ reported successful treatment of multiple familial trichoepitheliomas with vismodegib. Nonetheless, more studies are required to assess the efficacy and reliability of vismodegib in the management of adnexal tumors.

Recommended Dose of Vismodegib Therapy

The vismodegib dosage that is approved by the FDA is 150 mg/d until disease progression or the development of intolerable side effects.⁴ Higher dosing regimens were evaluated with 270 mg/d and 540 mg/d. No added therapeutic benefit was noted with the increase in the dose, and no dose-limiting toxic effects were observed.⁴¹

Management of Vismodegib Side Effects

Managing patient expectations is a crucial step in improving dysgeusia. The experience of dysgeusia varies among patients; thus, patients should be instructed to adjust their diets according to their level of dysgeusia, which can be achieved by changing ingredients or dressings used with their diet. This step has been proven to be effective in overcoming vismodegib-related dysgeusia. Also, fluid taste distortion may lead to dehydration and an increase in creatine level. Thus, patients should be encouraged to monitor fluid intake. Moreover, a treatment hiatus of 2 to 8 months results in near-complete improvement of taste distortion.

For muscle spasms, quinine, treatment break for 1 month, gentle exercise of affected areas, or muscle relaxants such as baclofen and temazepam all are effective methods. For vismodegib-related alopecia, managing patient expectations is key; patients should be aware that hair may take 6 to 12 months or even longer to regrow. In addition, shaving less frequently helps improve alopecia.

For gastrointestinal disorders, loperamide with or without codeine phosphate is effective in resolving diarrhea, and metoclopramide is mostly adequate in treating nausea. Another adverse event is weight loss; weight loss of 5% or more of total body weight prompts dietetic referral. If weight loss persists, a treatment break might be needed to regain weight.

Overall, treatment breaks are sufficient to resolve adverse events caused by vismodegib and do not compromise efficacy of treatment. The duration of a treatment break should be considered before initiation. In one clinical trial, a longer treatment break was associated with fewer adverse effects without affecting the efficacy of treatment.⁴²

Conclusion

Vismodegib provides an effective alternative to surgical intervention in the management of BCC. However, patients must be monitored vigilantly, as adverse events are common (>90%).

Basal cell carcinomas (BCCs) are considered the most common cutaneous cancers. Approximately 80% of nonmelanoma skin cancers are BCCs.^1,2 Surgical management is the gold standard for early-stage and localized BCCs; it may include simple excision vs Mohs micrographic surgery.^3,4 However, if left untreated, these lesions can progress to an advanced stage (locally advanced BCC) or infrequently may spread to distant sites (metastatic BCC). In the advanced stage, the lesions are no longer manageable by surgery or radiation therapy.^5,6 Recently, inhibitors targeting the hedgehog (Hh) pathway have shown great promise for these patients. The first drug approved by the US Food and Drug Administration (FDA) for locally advanced and metastatic BCC is vismodegib.⁷ In this article, we provide a clinical review of vismodegib for the management of BCC, including a discussion of the Hh pathway in BCC, adverse effects of vismodegib, use of vismodegib in adnexal skin tumors, recommended doses for vismodegib therapy in BCC, and management of the side effects of treatment.

Hh Pathway in BCC

In embryonic development, the Hh signaling pathway is crucial across a broad spectrum of species, including humans. Various members of the Hh family have been recognized, all working as secreted regulatory proteins.⁸ The name of the Hh signaling pathway is derived from a polypeptide ligand called hedgehog found in some fruit flies. Mutations in the gene led to fruit fly larvae that had a spiky hairy pattern of denticles similar to hedgehogs, leading to the name of this molecule.⁹ The transmembrane protein smoothened (SMO) is the main component of the Hh signaling pathway and initiates a signaling cascade that in turn leads to an increased expression of target genes, such as GLI1. Patched (PTCH), also a transmembrane protein and a cell-surface receptor for the secreted Hh ligand, suppresses the signaling capacity of SMO. Upon binding of the Hh ligand to the PTCH receptor, the suppression of SMO is relieved and a signal is propagated, evoking a cellular response.¹⁰ Molecular and genetic studies have reported that genetic alterations in the Hh signaling pathway are almost universally present in all BCCs, leading to an aberrant activation of the pathway and an uncontrolled proliferation of the basal cells. Frequently, these alterations have been shown to cause loss of function of PTCH homologue 1, which usually acts to inhibit the SMO homologue signaling activity.^11,12

Because of the potential importance of Hh signaling in other solid malignancies and the failure of topical inhibition of SMO,¹³ subsequent studies on the development of Hh pathway inhibitors have mostly focused on the systemic approach. A multitude of Hh pathway inhibitors have been developed thus far, such as SANT1-SANT4, GDC-0449, IPI-926, BMS-833923 (XL139), HhAntag-691, and MK-4101.¹⁴ Many of these inhibitors have been clinically investigated.^13,15,16

Systemic SMO Inhibitor: Vismodegib

Vismodegib was the earliest systemic SMO inhibitor to fulfill early clinical evaluation^15,16 and the first drug to receive FDA approval for the management of advanced or metastatic BCC. Vismodegib is a small-molecule SMO inhibitor used for the management of selected locally advanced BCC and metastatic BCC in adults.^3,17 Although there is a possibility of recurrence following drug withdrawal, vismodegib constitutes a new therapeutic strategy presenting positive benefits to patients. It may provide superior improvement over sunitinib, which has shown efficacy in a few patients; however, the efficacy and tolerance of sunitinib have been shown to be limited.^18,19

Adverse Effects of Vismodegib Therapy

Adverse events with vismodegib use have been reported in 98% of patients (N=491); most of these were mild to moderate.²⁰ However, the frequency of adverse events could prove to be a therapeutic challenge for patients requiring extended treatment. The most frequently reported reversible side effects were muscle spasms (64%), alopecia (62%), weight loss (33%), fatigue (28%), decreased appetite (25%), diarrhea (17%), nausea (16%), dysgeusia (54%), and ageusia (22%).²⁰ In clinical trials, amenorrhea was noticed in 30% (3/10) of females with reproductive potential.² Apart from alopecia and possibly amenorrhea, these side effects are reversible.¹⁷ Alkeraye et al¹⁷ reported 3 clinical cases of persistent alopecia following the use of vismodegib. Amenorrhea is a possible side effect of unknown reversibility.⁷

Vismodegib is a pregnancy category D medication.⁴ Severe birth defects, including craniofacial abnormalities, retardations in normal growth, open perineum, and absence of digital fusion at a corresponding 20% of the recommended daily dose, were found in rat studies. Embryo-fetal death was noted when rats were exposedto concentrations comparable to the recommended human dose.⁴

Hepatic events with the use of vismodegib have been reported. The use of vismodegib in randomized controlled trials resulted in elevation of both alanine aminotransferase and aspartate aminotransferase levels compared with placebo.²¹ Moreover, severe hepatotoxicity with vismodegib has been reported.^22-24 A study conducted by Edwards et al²⁵ concluded that the use of vismodegib in patients with severe liver disease must include thorough risk-benefit assessment, with caution in using other concomitant hepatotoxic medications.

Rare adverse events also have been reported in the literature, including vismodegib-induced pancreatitis in a 79-year-old patient treated for locally advanced, recurrent BCC that was cleared following cessation of therapy.²⁶ Additionally, atypical fibroxanthoma was observed in an 83-year-old patient after 30 days of treatment with vismodegib for multiple BCCs.²⁷ The development of other secondary malignancies, such as squamous cell carcinoma, melanoma, keratoacanthomas, and pilomatricomas, during or after the long-term use of vismodegib also have been described.^28-35

Use of Vismodegib for Adnexal Skin Tumors

The role of the sonic Hh–PTCH pathway in the pathogenesis of adnexal tumors varies in the literature. Some studies propose the involvement of this pathway in the formation of adnexal tumors such as trichoblastoma, trichoepithelioma, and cylindroma, as in BCC. Various lines of evidence support this involvement. Firstly, in mice, the spontaneous generation of numerous BCCs, trichoblastomas, trichoepitheliomas, and cylindromas has been observed following constitutive activation of the sonic Hh–PTCH pathway.³⁶ Secondly, in trichoepitheliomas, there have been positive results in molecular research into the tumor suppressor gene PTCH homologue 1, PTCH1, whose mutations cause constitutive activation of the sonic Hh–PTCH pathway.³⁷ Thirdly, GLI1³⁸ and SOX9³⁹ transcription factors associated with the signaling pathway of sonic Hh–PTCH appear to have increased levels in adnexal carcinomas.¹⁹ Lepesant et al¹⁹ reported a notable clinical response to vismodegib in trichoblastic carcinoma. Baur et al⁴⁰ reported successful treatment of multiple familial trichoepitheliomas with vismodegib. Nonetheless, more studies are required to assess the efficacy and reliability of vismodegib in the management of adnexal tumors.

Recommended Dose of Vismodegib Therapy

The vismodegib dosage that is approved by the FDA is 150 mg/d until disease progression or the development of intolerable side effects.⁴ Higher dosing regimens were evaluated with 270 mg/d and 540 mg/d. No added therapeutic benefit was noted with the increase in the dose, and no dose-limiting toxic effects were observed.⁴¹

Management of Vismodegib Side Effects

Managing patient expectations is a crucial step in improving dysgeusia. The experience of dysgeusia varies among patients; thus, patients should be instructed to adjust their diets according to their level of dysgeusia, which can be achieved by changing ingredients or dressings used with their diet. This step has been proven to be effective in overcoming vismodegib-related dysgeusia. Also, fluid taste distortion may lead to dehydration and an increase in creatine level. Thus, patients should be encouraged to monitor fluid intake. Moreover, a treatment hiatus of 2 to 8 months results in near-complete improvement of taste distortion.

For muscle spasms, quinine, treatment break for 1 month, gentle exercise of affected areas, or muscle relaxants such as baclofen and temazepam all are effective methods. For vismodegib-related alopecia, managing patient expectations is key; patients should be aware that hair may take 6 to 12 months or even longer to regrow. In addition, shaving less frequently helps improve alopecia.

For gastrointestinal disorders, loperamide with or without codeine phosphate is effective in resolving diarrhea, and metoclopramide is mostly adequate in treating nausea. Another adverse event is weight loss; weight loss of 5% or more of total body weight prompts dietetic referral. If weight loss persists, a treatment break might be needed to regain weight.

Overall, treatment breaks are sufficient to resolve adverse events caused by vismodegib and do not compromise efficacy of treatment. The duration of a treatment break should be considered before initiation. In one clinical trial, a longer treatment break was associated with fewer adverse effects without affecting the efficacy of treatment.⁴²

Conclusion

Vismodegib provides an effective alternative to surgical intervention in the management of BCC. However, patients must be monitored vigilantly, as adverse events are common (>90%).

Basal cell carcinomas (BCCs) are considered the most common cutaneous cancers. Approximately 80% of nonmelanoma skin cancers are BCCs.^1,2 Surgical management is the gold standard for early-stage and localized BCCs; it may include simple excision vs Mohs micrographic surgery.^3,4 However, if left untreated, these lesions can progress to an advanced stage (locally advanced BCC) or infrequently may spread to distant sites (metastatic BCC). In the advanced stage, the lesions are no longer manageable by surgery or radiation therapy.^5,6 Recently, inhibitors targeting the hedgehog (Hh) pathway have shown great promise for these patients. The first drug approved by the US Food and Drug Administration (FDA) for locally advanced and metastatic BCC is vismodegib.⁷ In this article, we provide a clinical review of vismodegib for the management of BCC, including a discussion of the Hh pathway in BCC, adverse effects of vismodegib, use of vismodegib in adnexal skin tumors, recommended doses for vismodegib therapy in BCC, and management of the side effects of treatment.

Hh Pathway in BCC

In embryonic development, the Hh signaling pathway is crucial across a broad spectrum of species, including humans. Various members of the Hh family have been recognized, all working as secreted regulatory proteins.⁸ The name of the Hh signaling pathway is derived from a polypeptide ligand called hedgehog found in some fruit flies. Mutations in the gene led to fruit fly larvae that had a spiky hairy pattern of denticles similar to hedgehogs, leading to the name of this molecule.⁹ The transmembrane protein smoothened (SMO) is the main component of the Hh signaling pathway and initiates a signaling cascade that in turn leads to an increased expression of target genes, such as GLI1. Patched (PTCH), also a transmembrane protein and a cell-surface receptor for the secreted Hh ligand, suppresses the signaling capacity of SMO. Upon binding of the Hh ligand to the PTCH receptor, the suppression of SMO is relieved and a signal is propagated, evoking a cellular response.¹⁰ Molecular and genetic studies have reported that genetic alterations in the Hh signaling pathway are almost universally present in all BCCs, leading to an aberrant activation of the pathway and an uncontrolled proliferation of the basal cells. Frequently, these alterations have been shown to cause loss of function of PTCH homologue 1, which usually acts to inhibit the SMO homologue signaling activity.^11,12

Because of the potential importance of Hh signaling in other solid malignancies and the failure of topical inhibition of SMO,¹³ subsequent studies on the development of Hh pathway inhibitors have mostly focused on the systemic approach. A multitude of Hh pathway inhibitors have been developed thus far, such as SANT1-SANT4, GDC-0449, IPI-926, BMS-833923 (XL139), HhAntag-691, and MK-4101.¹⁴ Many of these inhibitors have been clinically investigated.^13,15,16

Systemic SMO Inhibitor: Vismodegib

Vismodegib was the earliest systemic SMO inhibitor to fulfill early clinical evaluation^15,16 and the first drug to receive FDA approval for the management of advanced or metastatic BCC. Vismodegib is a small-molecule SMO inhibitor used for the management of selected locally advanced BCC and metastatic BCC in adults.^3,17 Although there is a possibility of recurrence following drug withdrawal, vismodegib constitutes a new therapeutic strategy presenting positive benefits to patients. It may provide superior improvement over sunitinib, which has shown efficacy in a few patients; however, the efficacy and tolerance of sunitinib have been shown to be limited.^18,19

Adverse Effects of Vismodegib Therapy

Adverse events with vismodegib use have been reported in 98% of patients (N=491); most of these were mild to moderate.²⁰ However, the frequency of adverse events could prove to be a therapeutic challenge for patients requiring extended treatment. The most frequently reported reversible side effects were muscle spasms (64%), alopecia (62%), weight loss (33%), fatigue (28%), decreased appetite (25%), diarrhea (17%), nausea (16%), dysgeusia (54%), and ageusia (22%).²⁰ In clinical trials, amenorrhea was noticed in 30% (3/10) of females with reproductive potential.² Apart from alopecia and possibly amenorrhea, these side effects are reversible.¹⁷ Alkeraye et al¹⁷ reported 3 clinical cases of persistent alopecia following the use of vismodegib. Amenorrhea is a possible side effect of unknown reversibility.⁷

Vismodegib is a pregnancy category D medication.⁴ Severe birth defects, including craniofacial abnormalities, retardations in normal growth, open perineum, and absence of digital fusion at a corresponding 20% of the recommended daily dose, were found in rat studies. Embryo-fetal death was noted when rats were exposedto concentrations comparable to the recommended human dose.⁴

Hepatic events with the use of vismodegib have been reported. The use of vismodegib in randomized controlled trials resulted in elevation of both alanine aminotransferase and aspartate aminotransferase levels compared with placebo.²¹ Moreover, severe hepatotoxicity with vismodegib has been reported.^22-24 A study conducted by Edwards et al²⁵ concluded that the use of vismodegib in patients with severe liver disease must include thorough risk-benefit assessment, with caution in using other concomitant hepatotoxic medications.

Rare adverse events also have been reported in the literature, including vismodegib-induced pancreatitis in a 79-year-old patient treated for locally advanced, recurrent BCC that was cleared following cessation of therapy.²⁶ Additionally, atypical fibroxanthoma was observed in an 83-year-old patient after 30 days of treatment with vismodegib for multiple BCCs.²⁷ The development of other secondary malignancies, such as squamous cell carcinoma, melanoma, keratoacanthomas, and pilomatricomas, during or after the long-term use of vismodegib also have been described.^28-35

Use of Vismodegib for Adnexal Skin Tumors

The role of the sonic Hh–PTCH pathway in the pathogenesis of adnexal tumors varies in the literature. Some studies propose the involvement of this pathway in the formation of adnexal tumors such as trichoblastoma, trichoepithelioma, and cylindroma, as in BCC. Various lines of evidence support this involvement. Firstly, in mice, the spontaneous generation of numerous BCCs, trichoblastomas, trichoepitheliomas, and cylindromas has been observed following constitutive activation of the sonic Hh–PTCH pathway.³⁶ Secondly, in trichoepitheliomas, there have been positive results in molecular research into the tumor suppressor gene PTCH homologue 1, PTCH1, whose mutations cause constitutive activation of the sonic Hh–PTCH pathway.³⁷ Thirdly, GLI1³⁸ and SOX9³⁹ transcription factors associated with the signaling pathway of sonic Hh–PTCH appear to have increased levels in adnexal carcinomas.¹⁹ Lepesant et al¹⁹ reported a notable clinical response to vismodegib in trichoblastic carcinoma. Baur et al⁴⁰ reported successful treatment of multiple familial trichoepitheliomas with vismodegib. Nonetheless, more studies are required to assess the efficacy and reliability of vismodegib in the management of adnexal tumors.

Recommended Dose of Vismodegib Therapy

The vismodegib dosage that is approved by the FDA is 150 mg/d until disease progression or the development of intolerable side effects.⁴ Higher dosing regimens were evaluated with 270 mg/d and 540 mg/d. No added therapeutic benefit was noted with the increase in the dose, and no dose-limiting toxic effects were observed.⁴¹

Management of Vismodegib Side Effects

Managing patient expectations is a crucial step in improving dysgeusia. The experience of dysgeusia varies among patients; thus, patients should be instructed to adjust their diets according to their level of dysgeusia, which can be achieved by changing ingredients or dressings used with their diet. This step has been proven to be effective in overcoming vismodegib-related dysgeusia. Also, fluid taste distortion may lead to dehydration and an increase in creatine level. Thus, patients should be encouraged to monitor fluid intake. Moreover, a treatment hiatus of 2 to 8 months results in near-complete improvement of taste distortion.

For muscle spasms, quinine, treatment break for 1 month, gentle exercise of affected areas, or muscle relaxants such as baclofen and temazepam all are effective methods. For vismodegib-related alopecia, managing patient expectations is key; patients should be aware that hair may take 6 to 12 months or even longer to regrow. In addition, shaving less frequently helps improve alopecia.

For gastrointestinal disorders, loperamide with or without codeine phosphate is effective in resolving diarrhea, and metoclopramide is mostly adequate in treating nausea. Another adverse event is weight loss; weight loss of 5% or more of total body weight prompts dietetic referral. If weight loss persists, a treatment break might be needed to regain weight.

Overall, treatment breaks are sufficient to resolve adverse events caused by vismodegib and do not compromise efficacy of treatment. The duration of a treatment break should be considered before initiation. In one clinical trial, a longer treatment break was associated with fewer adverse effects without affecting the efficacy of treatment.⁴²

Conclusion

Vismodegib provides an effective alternative to surgical intervention in the management of BCC. However, patients must be monitored vigilantly, as adverse events are common (>90%).

Practice Gap

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by inflammatory nodules, abscesses, sinus tracts, fistulae, and scarring, mainly in intertriginous areas. The extent of disease—classified using the Hurley staging system (stages I–III)—helps guide treatment, which includes medical management and surgical intervention in later stages.

First-line treatment of HS includes topical or systemic medications, or both. Surgical therapy typically is reserved for refractory HS in moderate to severe disease (Hurley stages II and III) and is combined with pharmacotherapy. Specifically, clinical management guidelines issued by an expert committee of the United States and Canadian Hidradenitis Suppurativa Foundations recommend excision or deroofing for recurrent nodules and tunnels.¹

Surgical options for HS that are available to the outpatient dermatologist include incision and drainage, electrosurgery, CO₂ laser evaporation, excision, and deroofing (also known as unroofing).² Deroofing is a fairly novel therapy; many dermatologists are unfamiliar with the procedure. A PubMed search of articles indexed for MEDLINE related to HS prior to 2010 revealed only 1 article containing the word deroofing and only 4 articles containing unroofing.

The pathophysiology of HS has important implications for successful treatment. Inflammation of the follicular pilosebaceous unit along with follicular occlusion create challenges with treatment.³ It is postulated that a defect in the glassy membrane of the infra-infundibular wall predisposes the pilosebaceous follicle to lose its structural integrality as pressure builds from plugging of the duct,⁴ which can result in the clinical hallmarks of HS including tunneling tracts, bridging nodules, abscesses, and fistulae that form with lateral expansion of the plugged follicle.

Leaking of the contents of these plugged follicles into surrounding tissue produces an inflammatory response in characteristic HS lesions. Because debris within the lesions moves laterally instead of being able to burst to the surface, the lesions have difficulty fully healing. Unroofing the lesions and removing built-up debris allows them to heal more expediently and quiets the underlying immune response by removing the stimulus.⁴

Herein, we describe the benefits, risks, and surgical process of deroofing for HS.

Technique and Tools

Deroofing is performed under local anesthesia, stepwise as follows:

1. Identify sinus tracts and infiltrate the area with lidocaine (Figure, A).

2. Use a blunt probe to define the borders of the area to be unroofed and to evaluate for any communicating sinus tracts (Figure, B).

3. Remove the roof of underlying abscesses and tracts, using a probe as a guide (Figure, C).

4. Enter through the skin or sinus opening using electrocautery or with a scalpel or scissors; perform blunt dissection.

5. Reflect back the entirety of skin overlying the probed areas and remove the skin to expose the base of the lesion (Figure, D).

6. Explore the exposed base and walls of the lesion with the probe again to assess for hidden tracts; take care not to create false tracts.

7. Debride the surgical wound using curettage or rough gauze grattage to remove remaining inflammatory debris or biofilm. To achieve hemostasis, apply aluminum chloride or ferric chloride. Coat the wound with petroleum jelly and gauze and allow it to heal by secondary intention.

8. Educate the patient on wound care—once-daily gentle cleansing with soap and water, followed by application of a moist dressing—which is similar to wound healing by secondary intention from other causes.^2,4

Practice Implications

A deroofing procedure has many benefits compared to other surgical modalities for the treatment of HS. Deroofing requires only a probe, curette, and electrocautery device, making the procedure more cost-effective than excision, which requires a full tray of equipment and sutures. Furthermore, margins do not need to be taken with deroofing, and no undermining or closure is needed, which saves time during the operation and minimizes the risk for complications, including dehiscence and formation of new sinus tracts.⁴ No specialized equipment, such as a CO₂ laser, is required, which makes deroofing accessible to every clinical dermatologist in any demographic or geographic setting.

Evidence of Benefit—Saylor and colleagues⁵ found that deroofing carries a 12.5% complication rate, which includes postoperative bleeding, hypergranulation tissue, and rarely wound infection. This rate is significantly lower than the 26% complication rate associated with local excision, which includes wound dehiscence, infection, and contracture (P<.001). Deroofing also was found to have an HS recurrence rate of 14.5%, which is significantly less than the 30% recurrence rate seen with local excision (P=.015). Saylor et al⁵ also concluded that incision and drainage was recommended only for immediate relief of HS because of its 100% recurrence rate.

van der Zee² reported on 88 lesions from 44 patients that were treated by surgical deroofing, resulting in an average defect of 3.0 cm in length and a mean healing time of 14 days. The typical outcome was cosmetically acceptable scarring; this finding was supported by a postoperative survey (>1 year), to which 37 of 44 patients responded and assigned an average satisfaction score of 8 (of a possible 10) and a recommendation rate of 90%.²

Procedural Coding—Specific Current Procedural Terminology codes (11450-11471) from the International Classification of Diseases, Tenth Revision, exist for HS deroofing procedures; the applicable code for a given case depends on the final length of the surgical defect. Documentation to support these codes is similar to the note for an excision procedure, taking care to include location, depth, and length of the excision; healing by secondary intention; and the diagnosis of HS.

Final Thoughts

Deroofing is a surgical option that can be beneficial to patients with HS. It is a relatively simple procedure available to any dermatologist, regardless of setting. We encourage dermatologists to consider deroofing, even in patients with Hurley stage II lesions, because it can yield cosmetically acceptable and definitive results, given the variety of therapies available for HS. Deroofing also can be superior to standard excision, especially because of the potential complications with standard excision and quicker operative time with deroofing. As more providers become familiar with the deroofing procedure for HS, further studies can be undertaken to add to the paucity of data about deroofing and how it compares to other surgical treatments.

Practice Gap

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by inflammatory nodules, abscesses, sinus tracts, fistulae, and scarring, mainly in intertriginous areas. The extent of disease—classified using the Hurley staging system (stages I–III)—helps guide treatment, which includes medical management and surgical intervention in later stages.

First-line treatment of HS includes topical or systemic medications, or both. Surgical therapy typically is reserved for refractory HS in moderate to severe disease (Hurley stages II and III) and is combined with pharmacotherapy. Specifically, clinical management guidelines issued by an expert committee of the United States and Canadian Hidradenitis Suppurativa Foundations recommend excision or deroofing for recurrent nodules and tunnels.¹

Surgical options for HS that are available to the outpatient dermatologist include incision and drainage, electrosurgery, CO₂ laser evaporation, excision, and deroofing (also known as unroofing).² Deroofing is a fairly novel therapy; many dermatologists are unfamiliar with the procedure. A PubMed search of articles indexed for MEDLINE related to HS prior to 2010 revealed only 1 article containing the word deroofing and only 4 articles containing unroofing.

The pathophysiology of HS has important implications for successful treatment. Inflammation of the follicular pilosebaceous unit along with follicular occlusion create challenges with treatment.³ It is postulated that a defect in the glassy membrane of the infra-infundibular wall predisposes the pilosebaceous follicle to lose its structural integrality as pressure builds from plugging of the duct,⁴ which can result in the clinical hallmarks of HS including tunneling tracts, bridging nodules, abscesses, and fistulae that form with lateral expansion of the plugged follicle.

Leaking of the contents of these plugged follicles into surrounding tissue produces an inflammatory response in characteristic HS lesions. Because debris within the lesions moves laterally instead of being able to burst to the surface, the lesions have difficulty fully healing. Unroofing the lesions and removing built-up debris allows them to heal more expediently and quiets the underlying immune response by removing the stimulus.⁴

Herein, we describe the benefits, risks, and surgical process of deroofing for HS.

Technique and Tools

Deroofing is performed under local anesthesia, stepwise as follows:

1. Identify sinus tracts and infiltrate the area with lidocaine (Figure, A).

2. Use a blunt probe to define the borders of the area to be unroofed and to evaluate for any communicating sinus tracts (Figure, B).

3. Remove the roof of underlying abscesses and tracts, using a probe as a guide (Figure, C).

4. Enter through the skin or sinus opening using electrocautery or with a scalpel or scissors; perform blunt dissection.

5. Reflect back the entirety of skin overlying the probed areas and remove the skin to expose the base of the lesion (Figure, D).

6. Explore the exposed base and walls of the lesion with the probe again to assess for hidden tracts; take care not to create false tracts.

7. Debride the surgical wound using curettage or rough gauze grattage to remove remaining inflammatory debris or biofilm. To achieve hemostasis, apply aluminum chloride or ferric chloride. Coat the wound with petroleum jelly and gauze and allow it to heal by secondary intention.

8. Educate the patient on wound care—once-daily gentle cleansing with soap and water, followed by application of a moist dressing—which is similar to wound healing by secondary intention from other causes.^2,4

Practice Implications

A deroofing procedure has many benefits compared to other surgical modalities for the treatment of HS. Deroofing requires only a probe, curette, and electrocautery device, making the procedure more cost-effective than excision, which requires a full tray of equipment and sutures. Furthermore, margins do not need to be taken with deroofing, and no undermining or closure is needed, which saves time during the operation and minimizes the risk for complications, including dehiscence and formation of new sinus tracts.⁴ No specialized equipment, such as a CO₂ laser, is required, which makes deroofing accessible to every clinical dermatologist in any demographic or geographic setting.

Evidence of Benefit—Saylor and colleagues⁵ found that deroofing carries a 12.5% complication rate, which includes postoperative bleeding, hypergranulation tissue, and rarely wound infection. This rate is significantly lower than the 26% complication rate associated with local excision, which includes wound dehiscence, infection, and contracture (P<.001). Deroofing also was found to have an HS recurrence rate of 14.5%, which is significantly less than the 30% recurrence rate seen with local excision (P=.015). Saylor et al⁵ also concluded that incision and drainage was recommended only for immediate relief of HS because of its 100% recurrence rate.

van der Zee² reported on 88 lesions from 44 patients that were treated by surgical deroofing, resulting in an average defect of 3.0 cm in length and a mean healing time of 14 days. The typical outcome was cosmetically acceptable scarring; this finding was supported by a postoperative survey (>1 year), to which 37 of 44 patients responded and assigned an average satisfaction score of 8 (of a possible 10) and a recommendation rate of 90%.²

Procedural Coding—Specific Current Procedural Terminology codes (11450-11471) from the International Classification of Diseases, Tenth Revision, exist for HS deroofing procedures; the applicable code for a given case depends on the final length of the surgical defect. Documentation to support these codes is similar to the note for an excision procedure, taking care to include location, depth, and length of the excision; healing by secondary intention; and the diagnosis of HS.

Final Thoughts

Deroofing is a surgical option that can be beneficial to patients with HS. It is a relatively simple procedure available to any dermatologist, regardless of setting. We encourage dermatologists to consider deroofing, even in patients with Hurley stage II lesions, because it can yield cosmetically acceptable and definitive results, given the variety of therapies available for HS. Deroofing also can be superior to standard excision, especially because of the potential complications with standard excision and quicker operative time with deroofing. As more providers become familiar with the deroofing procedure for HS, further studies can be undertaken to add to the paucity of data about deroofing and how it compares to other surgical treatments.

Practice Gap

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by inflammatory nodules, abscesses, sinus tracts, fistulae, and scarring, mainly in intertriginous areas. The extent of disease—classified using the Hurley staging system (stages I–III)—helps guide treatment, which includes medical management and surgical intervention in later stages.

First-line treatment of HS includes topical or systemic medications, or both. Surgical therapy typically is reserved for refractory HS in moderate to severe disease (Hurley stages II and III) and is combined with pharmacotherapy. Specifically, clinical management guidelines issued by an expert committee of the United States and Canadian Hidradenitis Suppurativa Foundations recommend excision or deroofing for recurrent nodules and tunnels.¹

Surgical options for HS that are available to the outpatient dermatologist include incision and drainage, electrosurgery, CO₂ laser evaporation, excision, and deroofing (also known as unroofing).² Deroofing is a fairly novel therapy; many dermatologists are unfamiliar with the procedure. A PubMed search of articles indexed for MEDLINE related to HS prior to 2010 revealed only 1 article containing the word deroofing and only 4 articles containing unroofing.

The pathophysiology of HS has important implications for successful treatment. Inflammation of the follicular pilosebaceous unit along with follicular occlusion create challenges with treatment.³ It is postulated that a defect in the glassy membrane of the infra-infundibular wall predisposes the pilosebaceous follicle to lose its structural integrality as pressure builds from plugging of the duct,⁴ which can result in the clinical hallmarks of HS including tunneling tracts, bridging nodules, abscesses, and fistulae that form with lateral expansion of the plugged follicle.

Leaking of the contents of these plugged follicles into surrounding tissue produces an inflammatory response in characteristic HS lesions. Because debris within the lesions moves laterally instead of being able to burst to the surface, the lesions have difficulty fully healing. Unroofing the lesions and removing built-up debris allows them to heal more expediently and quiets the underlying immune response by removing the stimulus.⁴

Herein, we describe the benefits, risks, and surgical process of deroofing for HS.

Technique and Tools

Deroofing is performed under local anesthesia, stepwise as follows:

1. Identify sinus tracts and infiltrate the area with lidocaine (Figure, A).

2. Use a blunt probe to define the borders of the area to be unroofed and to evaluate for any communicating sinus tracts (Figure, B).

3. Remove the roof of underlying abscesses and tracts, using a probe as a guide (Figure, C).

4. Enter through the skin or sinus opening using electrocautery or with a scalpel or scissors; perform blunt dissection.

5. Reflect back the entirety of skin overlying the probed areas and remove the skin to expose the base of the lesion (Figure, D).

6. Explore the exposed base and walls of the lesion with the probe again to assess for hidden tracts; take care not to create false tracts.

7. Debride the surgical wound using curettage or rough gauze grattage to remove remaining inflammatory debris or biofilm. To achieve hemostasis, apply aluminum chloride or ferric chloride. Coat the wound with petroleum jelly and gauze and allow it to heal by secondary intention.

8. Educate the patient on wound care—once-daily gentle cleansing with soap and water, followed by application of a moist dressing—which is similar to wound healing by secondary intention from other causes.^2,4

Practice Implications

A deroofing procedure has many benefits compared to other surgical modalities for the treatment of HS. Deroofing requires only a probe, curette, and electrocautery device, making the procedure more cost-effective than excision, which requires a full tray of equipment and sutures. Furthermore, margins do not need to be taken with deroofing, and no undermining or closure is needed, which saves time during the operation and minimizes the risk for complications, including dehiscence and formation of new sinus tracts.⁴ No specialized equipment, such as a CO₂ laser, is required, which makes deroofing accessible to every clinical dermatologist in any demographic or geographic setting.

Evidence of Benefit—Saylor and colleagues⁵ found that deroofing carries a 12.5% complication rate, which includes postoperative bleeding, hypergranulation tissue, and rarely wound infection. This rate is significantly lower than the 26% complication rate associated with local excision, which includes wound dehiscence, infection, and contracture (P<.001). Deroofing also was found to have an HS recurrence rate of 14.5%, which is significantly less than the 30% recurrence rate seen with local excision (P=.015). Saylor et al⁵ also concluded that incision and drainage was recommended only for immediate relief of HS because of its 100% recurrence rate.

van der Zee² reported on 88 lesions from 44 patients that were treated by surgical deroofing, resulting in an average defect of 3.0 cm in length and a mean healing time of 14 days. The typical outcome was cosmetically acceptable scarring; this finding was supported by a postoperative survey (>1 year), to which 37 of 44 patients responded and assigned an average satisfaction score of 8 (of a possible 10) and a recommendation rate of 90%.²

Procedural Coding—Specific Current Procedural Terminology codes (11450-11471) from the International Classification of Diseases, Tenth Revision, exist for HS deroofing procedures; the applicable code for a given case depends on the final length of the surgical defect. Documentation to support these codes is similar to the note for an excision procedure, taking care to include location, depth, and length of the excision; healing by secondary intention; and the diagnosis of HS.

Final Thoughts

Deroofing is a surgical option that can be beneficial to patients with HS. It is a relatively simple procedure available to any dermatologist, regardless of setting. We encourage dermatologists to consider deroofing, even in patients with Hurley stage II lesions, because it can yield cosmetically acceptable and definitive results, given the variety of therapies available for HS. Deroofing also can be superior to standard excision, especially because of the potential complications with standard excision and quicker operative time with deroofing. As more providers become familiar with the deroofing procedure for HS, further studies can be undertaken to add to the paucity of data about deroofing and how it compares to other surgical treatments.