Cutis

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Monilethrix

A diagnosis of monilethrix was rendered based on the clinical and trichoscopic findings. Simple surveillance of the patient’s condition and prevention of further hair trauma were proposed as management options.

Monilethrix is a hair shaft disorder that is inherited in a predominantly autosomal-dominant pattern with variable expressiveness and penetrance resulting from heterozygous mutations in hair keratin genes KRT81, KRT83, and KRT86 in a region of chromosome 12q13.13.^1,2 An autosomalrecessive form has been described with mutation in desmoglein 4, but it differs from the classical form by the variable periodicity of the region between the nodules.^3,4

The morphologic alteration consists of the formation of fusiform nodules of normal structure alternated with narrow and dystrophic constrictions (Figure). These internodes are fragile areas that cause breakage at constricted points.⁵ Clinically, monilethrix presents as areas of focal or diffuse alopecia with frequent involvement of the terminal follicles, mainly in areas of friction. The hair is normal at birth due to the predominance of lanugo in the neonatal period, but it subsequently is replaced by abnormal hairs in the first months of life.⁶ Initial clinical signs begin to appear when the terminal hairs begin to form.⁷ Although rarer, the eyebrows and eyelashes, as well as the axillary, pubic, and body hair, may be involved.⁵

Other hair shaft anomalies merit consideration in the differential diagnosis of monilethrix, including pseudomonilethrix, pressure alopecia, trichorrhexis invaginata, ectodermal dysplasia, tinea capitis, and trichothiodystrophy.⁶ The diagnosis is reached by clinical history and physical examination. Trichoscopy and light microscopy are used to confirm the diagnosis. Trichoscopic examination shows markedly higher rates of anagen hair. The shafts examined in our patient revealed 0.7- to 1-mm intervals between nodes. Hair can be better visualized under a polarized microscope, and the condition can be distinguished from pseudomonilethrix using this approach.^5,6 In our patient, the diagnosis was made based on light microscopy and trichoscopic findings with no genetic testing; however, genetic testing for the classic mutations of the keratin genes would be desirable to confirm the diagnosis but was not done in our patient.⁶ The prognosis of monilethrix is variable; most cases persist into adulthood, though spontaneous improvement may occur with advancing age, during summer, and during pregnancy.⁸

There is no definitive therapy for monilethrix. Although there have been reports of cases treated with systemic corticosteroids, oral retinoids, topical minoxidil, vitamins, and peeling ointments (desquamative oil), the cornerstone of management is protecting the hair against traumatic procedures such as excessive combing, brushing, and friction, as well as parent and patient education about the benign nature of the condition.9 Additionally, some cases have shown improvement with minoxidil solution at 2% and 5% concentrations, oral minoxidil, or acitretin.^7-9

The Diagnosis: Monilethrix

A diagnosis of monilethrix was rendered based on the clinical and trichoscopic findings. Simple surveillance of the patient’s condition and prevention of further hair trauma were proposed as management options.

Monilethrix is a hair shaft disorder that is inherited in a predominantly autosomal-dominant pattern with variable expressiveness and penetrance resulting from heterozygous mutations in hair keratin genes KRT81, KRT83, and KRT86 in a region of chromosome 12q13.13.^1,2 An autosomalrecessive form has been described with mutation in desmoglein 4, but it differs from the classical form by the variable periodicity of the region between the nodules.^3,4

The morphologic alteration consists of the formation of fusiform nodules of normal structure alternated with narrow and dystrophic constrictions (Figure). These internodes are fragile areas that cause breakage at constricted points.⁵ Clinically, monilethrix presents as areas of focal or diffuse alopecia with frequent involvement of the terminal follicles, mainly in areas of friction. The hair is normal at birth due to the predominance of lanugo in the neonatal period, but it subsequently is replaced by abnormal hairs in the first months of life.⁶ Initial clinical signs begin to appear when the terminal hairs begin to form.⁷ Although rarer, the eyebrows and eyelashes, as well as the axillary, pubic, and body hair, may be involved.⁵

Other hair shaft anomalies merit consideration in the differential diagnosis of monilethrix, including pseudomonilethrix, pressure alopecia, trichorrhexis invaginata, ectodermal dysplasia, tinea capitis, and trichothiodystrophy.⁶ The diagnosis is reached by clinical history and physical examination. Trichoscopy and light microscopy are used to confirm the diagnosis. Trichoscopic examination shows markedly higher rates of anagen hair. The shafts examined in our patient revealed 0.7- to 1-mm intervals between nodes. Hair can be better visualized under a polarized microscope, and the condition can be distinguished from pseudomonilethrix using this approach.^5,6 In our patient, the diagnosis was made based on light microscopy and trichoscopic findings with no genetic testing; however, genetic testing for the classic mutations of the keratin genes would be desirable to confirm the diagnosis but was not done in our patient.⁶ The prognosis of monilethrix is variable; most cases persist into adulthood, though spontaneous improvement may occur with advancing age, during summer, and during pregnancy.⁸

There is no definitive therapy for monilethrix. Although there have been reports of cases treated with systemic corticosteroids, oral retinoids, topical minoxidil, vitamins, and peeling ointments (desquamative oil), the cornerstone of management is protecting the hair against traumatic procedures such as excessive combing, brushing, and friction, as well as parent and patient education about the benign nature of the condition.9 Additionally, some cases have shown improvement with minoxidil solution at 2% and 5% concentrations, oral minoxidil, or acitretin.^7-9

The Diagnosis: Monilethrix

A diagnosis of monilethrix was rendered based on the clinical and trichoscopic findings. Simple surveillance of the patient’s condition and prevention of further hair trauma were proposed as management options.

Monilethrix is a hair shaft disorder that is inherited in a predominantly autosomal-dominant pattern with variable expressiveness and penetrance resulting from heterozygous mutations in hair keratin genes KRT81, KRT83, and KRT86 in a region of chromosome 12q13.13.^1,2 An autosomalrecessive form has been described with mutation in desmoglein 4, but it differs from the classical form by the variable periodicity of the region between the nodules.^3,4

The morphologic alteration consists of the formation of fusiform nodules of normal structure alternated with narrow and dystrophic constrictions (Figure). These internodes are fragile areas that cause breakage at constricted points.⁵ Clinically, monilethrix presents as areas of focal or diffuse alopecia with frequent involvement of the terminal follicles, mainly in areas of friction. The hair is normal at birth due to the predominance of lanugo in the neonatal period, but it subsequently is replaced by abnormal hairs in the first months of life.⁶ Initial clinical signs begin to appear when the terminal hairs begin to form.⁷ Although rarer, the eyebrows and eyelashes, as well as the axillary, pubic, and body hair, may be involved.⁵

Other hair shaft anomalies merit consideration in the differential diagnosis of monilethrix, including pseudomonilethrix, pressure alopecia, trichorrhexis invaginata, ectodermal dysplasia, tinea capitis, and trichothiodystrophy.⁶ The diagnosis is reached by clinical history and physical examination. Trichoscopy and light microscopy are used to confirm the diagnosis. Trichoscopic examination shows markedly higher rates of anagen hair. The shafts examined in our patient revealed 0.7- to 1-mm intervals between nodes. Hair can be better visualized under a polarized microscope, and the condition can be distinguished from pseudomonilethrix using this approach.^5,6 In our patient, the diagnosis was made based on light microscopy and trichoscopic findings with no genetic testing; however, genetic testing for the classic mutations of the keratin genes would be desirable to confirm the diagnosis but was not done in our patient.⁶ The prognosis of monilethrix is variable; most cases persist into adulthood, though spontaneous improvement may occur with advancing age, during summer, and during pregnancy.⁸

There is no definitive therapy for monilethrix. Although there have been reports of cases treated with systemic corticosteroids, oral retinoids, topical minoxidil, vitamins, and peeling ointments (desquamative oil), the cornerstone of management is protecting the hair against traumatic procedures such as excessive combing, brushing, and friction, as well as parent and patient education about the benign nature of the condition.9 Additionally, some cases have shown improvement with minoxidil solution at 2% and 5% concentrations, oral minoxidil, or acitretin.^7-9

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

To the Editor:

Granulomatous dermatitis (GD) has been described as a rare side effect of MEK and BRAF inhibitor use in the treatment of BRAF V600E mutation–positive metastatic melanoma. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation. We present the case of a 52-year-old woman who developed GD while being treated with vemurafenib and cobimetinib for BRAF V600E mutation–positive metastatic cholangiocarcinoma.

A 52-year-old White woman presented with faint patches of nonpalpable violaceous mottling that extended distally to proximally from the ankles to the thighs on the medial aspects of both legs. She was diagnosed with cholangiocarcinoma 10 months prior, with metastases to the lung, liver, and sternum. She underwent treatment with gemcitabine and cisplatin therapy. Computed tomography after several treatment cycles revealed progressive disease with multiple pulmonary nodules as well as metastatic intrathoracic and abdominal adenopathy. Treatment with gemcitabine and cisplatin failed to produce a favorable response and was discontinued after 6 treatment cycles.

Genomic testing performed at the time of diagnosis revealed a positive mutation for BRAF V600E. The patient subsequently enrolled in a clinical trial and started treatment with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. She developed sun sensitivity and multiple sunburns after starting these therapies. The patient tolerated the next few cycles of therapy well with only moderate concerns of dry sensitive skin.

During the sixth cycle of therapy, she presented to dermatology after developing a rash. Over the next 2 weeks, similar lesions appeared on the arms. The patient denied the use of any new lotions, soaps, or other medications. Punch biopsies of the right forearm and right medial thigh revealed nonnecrotizing granulomas in the superficial dermis that extended into the subcutaneous adipose tissue (Figure 1). Surrounding chronic inflammation was scant, and the presence of rare eosinophils was noted (Figure 2). The histiocytes were highlighted by a CD68 immunohistochemical stain. An auramine-O special stain test was negative for acid-fast bacilli, and a Grocott methenamine-silver special stain test for fungal organisms was negative. These findings were consistent with GD. Computed tomography of the chest performed 2 months prior and 1 month after biopsy of the skin lesions revealed no axillary, mediastinal, or hilar lymphadenopathy. The calcium level at the time of skin biopsy was within reference range.

A topical steroid was prescribed; however, it was not utilized by the patient. Within 2 months of onset, the GD lesions resolved with no treatment. The GD lesions did not affect the patient’s enrollment in the clinical trial, and no dose reductions were made. Due to progressive disease with metastases to the brain, the patient eventually discontinued the clinical trial.

BRAF inhibitors are US Food and Drug Administration approved for the treatment of metastatic melanoma to deactivate the serine-threonine kinase BRAF gene mutation, which leads to decreased generation and survival of melanoma cells.^1,2 Vemurafenib, dabrafenib, and encorafenib are the only BRAF inhibitors approved in the United States.³ The most common side effects of vemurafenib include arthralgia, fatigue, rash, and photosensitivity.^1,4 There are 4 MEK inhibitors currently available in the United States: cobimetinib, trametinib, selumetinib and binimetinib. The addition of a MEK inhibitor to BRAF inhibitor therapy has shown increased patient response rates and prolonged survival in 3 phase 3 studies.^5-10

Response rates remain low in the treatment of advanced cholangiocarcinoma with standard chemotherapy. Recent research has explored if targeted therapies at the molecular level would be of benefit.¹¹ Our patient was enrolled in the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry (TAPUR) trial, a phase 2, prospective, nonrandomized trial that matches eligible participants to US Food and Drug Administration–approved study medications based on specific data from their molecular testing results.¹² Some of the most common mutations in intrahepatic cholangiocarcinoma include HER2, KRAS, MET, and BRAF.^13-17 Our patient’s molecular test results were positive for a BRAF V600E–positive mutation, and she subsequently started therapy with vemurafenib and cobimetinib. The use of personalized genomic treatment approaches for BRAF V600E mutation–positive cholangiocarcinoma has produced a dramatic patient response to BRAF and MEK inhibitor combination therapies.^11,18-20

Drug-induced GD most likely is caused by vascular insults that lead to deposition of immune complexes in vessels causing inflammation and a consequent granulomatous infiltrate.^21,22 Although cordlike lesions in the subcutaneous tissue on the trunk commonly are reported, the presentation of GD can vary considerably. Other presentations include areas of violaceous or erythematous patches or plaques on the limbs, intertriginous areas, and upper trunk. Diffuse macular erythema or small flesh-colored papules also can be observed.²³

Granulomatous dermatitis secondary to drug reactions can have varying morphologies. The infiltrate often can have an interstitial appearance with the presence of lymphocytes, plasma cells, histiocytes, eosinophils, and multinucleated giant cells.²⁴ These findings can be confused with interstitial granuloma annulare. Other cases, such as in our patient, can have discrete granulomata formation with a sarcoidlike appearance. These naked granulomas lack surrounding inflammation and suggest a differential diagnosis of sarcoidosis and infection. Use of immune checkpoint inhibitors (CIs) and kinase inhibitors has been proven to cause sarcoidosislike reactions.²⁵ The development of granulomatous/sarcoidlike lesions associated with the use of BRAF and MEK inhibitors may clinically and radiographically mimic disease recurrence. An awareness of this type of reaction by clinicians and pathologists is important to ensure appropriate management in patients who develop GD.²⁶

Checkpoint inhibitor–induced GD that remains asymptomatic does not necessarily warrant treatment; however, corticosteroid use and elimination of CI therapies have resolved GD in prior cases. Responsiveness of the cancer to CI therapy and severity of GD symptoms should be considered before discontinuation of a CI trial.²⁵

One case report described complete resolution of a GD eruption without interruption of the scheduled BRAF and MEK inhibitor therapies for the treatment of metastatic melanoma. There was no reported use of a steroidal cream or other topical medication to aid in controlling the eruption.²⁷ The exact mechanism of how GD resolves while continuing therapy is unknown; however, it has been suggested that a GD eruption may be the consequence of a BRAF and MEK inhibitor–mediated immune response against a subclinical area of metastatic melanoma.²⁸ If the immune response successfully eliminates the subclinical tumor, one could postulate that the inflammatory response and granulomatous eruption would resolve. Future studies are necessary to further elucidate the exact mechanisms involved.

There have been several case reports of GD with vemurafenib treatment,^29,30 1 report of GD and erythema induratum with vemurafenib and cobimetinib treatment,³¹ 2 reports of GD with dabrafenib treatment,^27,30 and a few reports of GD with the BRAF inhibitor dabrafenib combined with the MEK inhibitor trametinib,^28,32,33 all for the treatment of metastatic melanoma. Additionally, a report described a 3-year-old boy who developed GD secondary to vemurafenib for the treatment of Langerhans cell histiocytosis.³⁴ We present a unique case of BRAF and MEK inhibitor therapy–induced GD in the treatment of metastatic cholangiocarcinoma with vemurafenib and cobimetinib.

BRAF and MEK inhibitor therapy is used in patients with metastatic melanomas with a positive BRAF V600E mutation. Due to advancements in next-generation DNA sequencing, these therapies also are being tested in clinical trials for use in the treatment of other cancers with the same checkpoint mutation, such as metastatic cholangiocarcinoma. Cutaneous reactions frequently are documented side effects that occur during treatment with BRAF and MEK inhibitors; GD is an uncommon finding. As the utilization of BRAF and MEK inhibitors increases for the treatment of a variety of other cancers, it is essential that clinicians and pathologists recognize GD as a potential cutaneous manifestation.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Atopic dermatitis (AD) and psoriasis are common skin diseases in which dysfunction of the epidermal barrier leads to skin inflammation and altered expression of proinflammatory cytokines.¹ There often is overlap in the clinical and histopathologic features of AD and psoriasis, which can make diagnosis a challenge. Persistent late-stage AD can present with psoriasiform lichenified changes, and psoriasis lesions in the acute stage can have an eczematous appearance.² Histologically, chronic psoriasis lesions share many overlapping features with AD, and some subsets of AD with IL-17 predominance (ie, intrinsic, pediatric, presentation in Asian patients) exhibit a psoriasiform appearance.^3,4

Atopic dermatitis and psoriasis are considered 2 distinct conditions because AD is a helper T cell (T_H2)–driven disease with subsequent overproduction of IL-4 and IL-13 and psoriasis is a T_H17 cell–driven disease with overproduction of IL-17³; however, the shared features of AD and psoriasis represent an underlying immunopathological spectrum^2,5,6 in which one condition can develop following treatment of the other condition (immunological shift in pathways), both conditions can occur at different times in a patient’s life with alternating cycles of disease flares, or both conditions can coexist as an overlapping syndrome.^1,2 A retrospective study from 2012 to 2019 estimated the prevalence of concomitant AD and psoriasis in the United States at 1.3%, with AD following the diagnosis of psoriasis in 67% of cases.¹ Concurrent AD and psoriasis—when both diseases flaresimultaneously—is the rarest scenario.^2,5

Treatment modalities for AD include topical corticosteroids, which act on immune cells to suppress the release of proinflammatory cytokines, as well as dupilumab, which offers targeted blockade of involved cytokines IL-4 and IL-13. Psoriasis can be treated with multiple immune modulators, including topical corticosteroids and vitamin D analogs, as well as systemic medications that reduce T-cell activation and inflammatory cytokines through targeting of IFN-γ, IL-2, tumor necrosis factor α, IL-17, and IL-23.^7,8

We present the case of a patient with long-standing concurrent, treatment-resistant AD and psoriasis who was successfully treated with dual biologic therapy with guselkumab and dupilumab.

Case Report

A 62-year-old woman presented to our dermatology clinic with red itchy scales and painful fissures on the palms, hands, and soles of more than 12 years’ duration. Her medical history included an allergy to amoxicillin-clavulanate as well as an allergy to both dog and cat dander on prick testing. Her family history included dyshidrotic eczema in her mother. A complete blood cell count with differential was within reference range. A shave biopsy of the right dorsal hand performed at the onset of symptoms at an outside facility revealed hyperkeratotic acanthotic epidermis with a mild perivascular lymphocytic infiltrate.

Results of patch testing indicated contact hypersensitivity to the botanical rosin colophonium (or colophony); carba mix (1, 3-diphenylguanidine, zinc dibutyldithiocarbamate, and zinc diethydithiocarbamate); thiuram mix (tetramethylthiuram disulfide, tetramethylthiuram monosulfide, and tetraethylthiuram disulfide); n,n-diphenylguanidine; and tixocortol-21-pivalate. Our patient was given guidance on avoiding these agents, as it was suspected that exposure may be exacerbating the psoriasis. The psoriasis was treated with topical corticosteroids, keratolytics, and calcineurin inhibitors, all of which offered minimal or no relief. Trials of systemic agents, including methotrexate (discontinued because transaminitis developed), etanercept, adalimumab, and apremilast for 6 to 10 months did not provide improvement.

Two years prior to the current presentation, our patient had been treated with the IL-23 inhibitor guselkumab, which provided moderate improvement. When she presented to our clinic, physical examination while she was taking guselkumab demonstrated prurigo with excoriations of the extremities, hyperkeratosis with scaling and fissures of the soles, erythematous scaly plaques on the palms and dorsal surface of the hands, and mild onycholysis of the nails (Figures 1 and 2). Because we were concerned about concomitant intrinsic AD, dupilumab was initiated in conjunction with guselkumab. A second biopsy was considered but deferred in favor of clinical monitoring.

After 1 year of dual biologic therapy, the patient experienced near-complete resolution of symptoms. The psoriasis completely resolved from an initial body surface area of 5%, and the AD body surface area decreased from 30% to 2% (Figure 3). The patient reported no adverse effects from treatment.

Comment

Atopic dermatitis and psoriasis involve complex immunopathology and a spectrum of cytokines that might explain the overlap in their clinical and histopathologic presentations.

Atopic dermatitis—Atopic dermatitis involves T_H1, T_H2, T_H9, T_H17, and T_H22 cells; T_H2 cells release IL-4, IL-5, and IL-13, all of which are key cytokines in the inflammatory pathway of AD.^9,10 Activation of the helper T-cell subset and the release of cytokines differ slightly based on the subcategory of AD and the stage of exacerbation. In addition to T_H2-cell activation, T_H1 cells and T_H22 cells—which release IL-12 and IL-22, respectively—are active in both intrinsic and extrinsic AD. T_H17 cells and T_H9 cells—which release IL-17 and IL-9, respectively—are more prominent in the intrinsic pathway than in the extrinsic pathway.⁹ Intrinsic AD is recognized by a lack of eosinophilia, female predominance, and delayed onset compared to extrinsic AD; there also is a lack of history of atopy.¹ Extrinsic AD is characterized by eosinophilia as well as a personal and family history of atopy.¹¹ Our patient—a female with onset in older adulthood, lack of eosinophilia, and a family history of atopy—displayed features of both intrinsic and extrinsic AD.

Psoriasis—The immunopathology of psoriasis involves stimulation of dendritic cells, which activate T_H17 cells through IL-23. T_H17 cells then release IL-17 and IL-22. Therefore, both AD and psoriasis involve activation of T_H22 and T_H1 cells, with increased IL-17 and IL-22 production.^3,10,12 IL-17 and IL-22 induce epidermal hyperplasia; IL-22 also contributes to skin barrier dysfunction.¹² Therefore, it might be reasonable to consider psoriasis and AD as diseases that exist across a T-cell axis spectrum, thereby accounting for some overlap in disease characteristics.³

Dual Biologic Therapy—Dupilumab blocks the IL-4 receptor α subunit, a receptor for IL-4 and IL-13, which are key cytokines in the pathogenesis of AD.¹⁰ Guselkumab inhibits IL-23, thus blocking the inflammatory cascade of T_H17 cell activation and release of IL-17 and IL-22 in the psoriasis pathway.¹³ Although an immunopathological spectrum exists between the 2 diseases, the continued presence of AD symptoms after blocking the IL-23 cascade suggests that additional blockade of T_H2 cells is required to control AD in patients with true concurrent disease.

Accurate diagnosis of AD and/or psoriasis is important when considering targeted treatment of these conditions with biologics. The use of dual biologics is limited by a paucity of data regarding the safety of these agents when given in combination. A recent meta-analysis of dual biologic therapy in patients with inflammatory bowel disease demonstrated acceptable safety results with a pooled adverse reaction rate of 31%.¹⁴

Anchoring Bias—Anchoring bias can occur when a clinician’s decisions are influenced by a particular event or reference point, which might cause them to disregard subsequent evidence. Our case illustrates the importance of critically assessing the response to treatment and being mindful of the potential influence of anchoring bias on the differential diagnosis. Although overcoming biases in conditions with clinical overlap can be challenging, it is important to consider coexisting AD and psoriasis in patients with extensive hand involvement when multiple treatments have failed and only a partial response to targeted pathways has been achieved. In our case, the patient also had contact hypersensitivity to tixocortol-21-pivalate, which indicates hypersensitivity to many prescription topical corticosteroids, oral prednisone, and over-the-counter hydrocortisone; however, topical corticosteroids continued to be prescribed for her, which might have contributed to the lack of improvement and even exacerbated the rash.

Future Considerations—A consideration for the future in this case is discontinuing guselkumab to observe whether symptoms recur. We discussed this option with the patient, but she opted to continue treatment with dupilumab and guselkumab because of the symptom resolution.

Conclusion

Concomitant disease can present as an overlapping pattern in the same area, whereas other regions might have geographically isolated disease. Our patient’s overlap of symptoms, the failure of multiple treatments, and the partial improvement she experienced on guselkumab made diagnosis and management challenging; however, dual biologic therapy was successful.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) and primary cutaneous mucinous carcinoma (PCMC) are rare low-grade neoplasms thought to arise from apocrine glands. These neoplasms share many histologic features and are proposed to be on a single histopathologic continuum, with EMPSGC as the in situ form that may progress to the invasive PCMC,¹ which is analogous to ductal carcinoma in situ and mucinous carcinoma of the breast, respectively.^2-5 Management involves a metastatic workup and either wide local excision (WLE) with margins greater than 5 mm or Mohs micrographic surgery (MMS) in anatomically sensitive areas.² We present 2 cases of EMPSGC and 3 cases of PCMC. We also review the clinical and histopathological features, differential diagnoses, and treatments.

Methods

Following institutional review board approval, we conducted a retrospective, single-institution case series. We searched electronic medical records dating from 2000 to 2019 for tumors diagnosed as PCMC or extramammary Paget disease treated with MMS. We gathered demographic, clinical, pathologic, and follow-up information from the electronic medical records for each case (Tables 1 and 2). Two dermatopathologists (B.P. and B.F.K.) reviewed the hematoxylin and eosin–stained slides of each tumor as well as all available immunohistochemical stains. One of the reviewers (B.F.K.) is a board-certified dermatologist, dermatopathologist, and fellowship-trained Mohs surgeon.

Results

Demographic and Clinical Information—We identified 2 cases of EMPSGC and 3 cases of PCMC diagnosed and treated at our institution; 4 of these cases had been treated within the last 2 years. One had been treated 18 years prior; case information was limited due to planned institutional record destruction. Three of the patients were female and 2 were male. The mean age at presentation was 71 years (range, 62–87 years). None had experienced recurrence or metastases after a mean follow-up of 30 months.

Case 1—A 68-year-old woman noted a slow-growing, flesh-colored papule measuring 12×10 mm on the right lower eyelid. An excisional biopsy was completed with 2-mm clinical margins, and the defect was closed in a linear fashion. Histologic sections demonstrated EMPSGC with uninvolved margins. The patient desired no further intervention and was clinically followed. Magnetic resonance imaging (MRI) of the head and neck found no evidence of metastasis. She has had no recurrence after 15 months.

Case 2—A 62-year-old man presented with a 7×5-mm, flesh-colored papule on the left lower eyelid margin (Figure 1). It was previously treated conservatively as a hordeolum but was biopsied after it failed to resolve with 3-mm margins. Histopathology demonstrated an EMPSGC (Figure 2). The lesion was treated with modified MMS with permanent en face section processing and cleared after 1 stage. Computed tomography of the head and neck showed no abnormalities. He has had no recurrence after 9 months.

Case 3—A 72-year-old man presented with a nontender papule near the right lateral canthus. A punch biopsy demonstrated PCMC. He was treated via modified MMS with permanent en face section processing. The tumor was cleared in 1 stage. He showed no evidence of recurrence after 112 months and died of unrelated causes. The rest of his clinical information was limited because of planned institutional destruction of records.

Case 4—An 87-year-old woman presented with a 25×25-mm, slow-growing mass of 12 months’ duration on the left lower abdomen (Figure 3). A biopsy demonstrated PCMC (Figure 4). Because of the size of the lesion, she underwent WLE with 20- to 30-mm margins by a general surgeon under general anesthesia. Positron emission tomography/computed tomography was unremarkable. She has remained disease free for 11 months.

Case 5—A 66-year-old woman presented for evaluation of a posterior scalp mass measuring 23×18 mm that had grown over the last 24 months. Biopsy showed mucinous carcinoma with lymphovascular invasion consistent with PCMC (Figure 5) confirmed on multiple tissue levels and with the aid of immunohistochemistry. She was sent for an MRI of the head, neck, chest, abdomen, and pelvis, which demonstrated 2 enlarged postauricular lymph nodes and raised suspicion for metastatic disease vs reactive lymphadenopathy. Mohs micrographic surgery with frozen sections was performed with 1- to 3-mm margins; the final layer was sent for permanent processing and confirmed negative margins. Sentinel lymph node biopsy and lymphadenectomy of the 2 nodes present on imaging showed no evidence of metastasis. The patient had no recurrence in 1 month.

Comment

Endocrine mucin-producing sweat gland carcinoma and PCMC are sweat gland malignancies that carry low metastatic potential but are locally aggressive. Endocrine mucin-producing sweat gland carcinoma has a strong predilection for the periorbital region, especially the lower eyelids of older women.³ Primary cutaneous mucinous carcinoma may arise on the eyelids, scalp, axillae, and trunk and has been reported more often in older men. These slow-growing tumors appear as nonspecific nodules.³ Lesions frequently are asymptomatic but rarely may cause pruritus and bleeding. Histologically, EMPSGC appears as solid or cystic nodules of cells with a papillary, cribriform, or pseudopapillary appearance. Intracellular or extracellular mucin as well as malignant spread of tumor cells along pre-existing ductlike structures make it difficult to histologically distinguish EMPSGC from ductal carcinoma in situ.³

A key histopathologic feature of PCMC is basophilic epithelioid cell nests in mucinous lakes.⁴ Rosettelike structures are seen within solid areas of the tumor. Fibrous septae separate individual collections of mucin, creating a lobulated appearance. The histopathologic differential diagnosis of EMPSGC and PCMC is broad, including basal cell carcinoma, hidradenoma, hidradenocarcinoma, apocrine adenoma, and dermal duct tumor. Positive expression of at least 1 neuroendocrine marker (ie, synaptophysin, neuron-specific enolase, chromogranin) and low-molecular cytokeratin (cytokeratin 7, CAM5.2, Ber-EP4) can aid in the diagnosis of both EMPSGC and PCMC.⁴ The use of p63 immunostaining is beneficial in delineating adnexal neoplasms. Adnexal tumors that stain positively with p63 are more likely to be of primary cutaneous origin, whereas lack of p63 staining usually denotes a secondary metastatic process. However, p63 staining is less reliable when distinguishing primary and metastatic mucinous neoplasms. Metastatic mucinous carcinomas often stain positive with p63, while PCMC usually stains negative despite its primary cutaneous origin, decreasing the clinical utility of p63. The tumor may be identical to metastatic mucinous adenocarcinoma of the breast, gastrointestinal tract, lung, ovary, and pancreas. Tumor islands floating in mucin are identified in both primary cutaneous and metastatic disease to the skin.^3,6 Areas of tumor necrosis, notable atypia, and perineural or lymphovascular invasion are infrequently reported in EMPSGC or PCMC, though lymphatic invasion was identified in case 5 presented herein.

A metastatic workup is warranted in all cases of PCMC, including a thorough history, review of systems, breast examination, and imaging. A workup may be considered in cases of EMPSGC depending on histologic features or clinical history.

There is uncertainty regarding the optimal management of these slow-growing yet locally destructive tumors.⁵ The incidence of local recurrence of PCMC after WLE with narrow margins of at least 1 cm can be as high as 30% to 40%, especially on the eyelid.⁴ There is no consensus on surgical care for either of these tumors.⁵ Because of the high recurrence rate and the predilection for the eyelid and face, MMS provides an excellent alternative to WLE for tissue preservation and meticulous margin control. We advocate for the use of the Mohs technique with permanent sectioning, which may delay the repair, but reviewing tissue with permanent fixation improves the quality and accuracy of the margin evaluation because these tumors often are infiltrative and difficult to delineate under frozen section processing. Permanent en face sectioning allows the laboratory to utilize the full array of immunohistochemical stains for these tumors, providing accurate and timely results.

Limitations to our retrospective uncontrolled study include missing or incomplete data points and short follow-up time. Additionally, there was no standardization to the margins removed with MMS or WLE because of the limited available data that comment on appropriate margins.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) and primary cutaneous mucinous carcinoma (PCMC) are rare low-grade neoplasms thought to arise from apocrine glands. These neoplasms share many histologic features and are proposed to be on a single histopathologic continuum, with EMPSGC as the in situ form that may progress to the invasive PCMC,¹ which is analogous to ductal carcinoma in situ and mucinous carcinoma of the breast, respectively.^2-5 Management involves a metastatic workup and either wide local excision (WLE) with margins greater than 5 mm or Mohs micrographic surgery (MMS) in anatomically sensitive areas.² We present 2 cases of EMPSGC and 3 cases of PCMC. We also review the clinical and histopathological features, differential diagnoses, and treatments.

Methods

Following institutional review board approval, we conducted a retrospective, single-institution case series. We searched electronic medical records dating from 2000 to 2019 for tumors diagnosed as PCMC or extramammary Paget disease treated with MMS. We gathered demographic, clinical, pathologic, and follow-up information from the electronic medical records for each case (Tables 1 and 2). Two dermatopathologists (B.P. and B.F.K.) reviewed the hematoxylin and eosin–stained slides of each tumor as well as all available immunohistochemical stains. One of the reviewers (B.F.K.) is a board-certified dermatologist, dermatopathologist, and fellowship-trained Mohs surgeon.

Results

Demographic and Clinical Information—We identified 2 cases of EMPSGC and 3 cases of PCMC diagnosed and treated at our institution; 4 of these cases had been treated within the last 2 years. One had been treated 18 years prior; case information was limited due to planned institutional record destruction. Three of the patients were female and 2 were male. The mean age at presentation was 71 years (range, 62–87 years). None had experienced recurrence or metastases after a mean follow-up of 30 months.

Case 1—A 68-year-old woman noted a slow-growing, flesh-colored papule measuring 12×10 mm on the right lower eyelid. An excisional biopsy was completed with 2-mm clinical margins, and the defect was closed in a linear fashion. Histologic sections demonstrated EMPSGC with uninvolved margins. The patient desired no further intervention and was clinically followed. Magnetic resonance imaging (MRI) of the head and neck found no evidence of metastasis. She has had no recurrence after 15 months.

Case 2—A 62-year-old man presented with a 7×5-mm, flesh-colored papule on the left lower eyelid margin (Figure 1). It was previously treated conservatively as a hordeolum but was biopsied after it failed to resolve with 3-mm margins. Histopathology demonstrated an EMPSGC (Figure 2). The lesion was treated with modified MMS with permanent en face section processing and cleared after 1 stage. Computed tomography of the head and neck showed no abnormalities. He has had no recurrence after 9 months.

Case 3—A 72-year-old man presented with a nontender papule near the right lateral canthus. A punch biopsy demonstrated PCMC. He was treated via modified MMS with permanent en face section processing. The tumor was cleared in 1 stage. He showed no evidence of recurrence after 112 months and died of unrelated causes. The rest of his clinical information was limited because of planned institutional destruction of records.

Case 4—An 87-year-old woman presented with a 25×25-mm, slow-growing mass of 12 months’ duration on the left lower abdomen (Figure 3). A biopsy demonstrated PCMC (Figure 4). Because of the size of the lesion, she underwent WLE with 20- to 30-mm margins by a general surgeon under general anesthesia. Positron emission tomography/computed tomography was unremarkable. She has remained disease free for 11 months.

Case 5—A 66-year-old woman presented for evaluation of a posterior scalp mass measuring 23×18 mm that had grown over the last 24 months. Biopsy showed mucinous carcinoma with lymphovascular invasion consistent with PCMC (Figure 5) confirmed on multiple tissue levels and with the aid of immunohistochemistry. She was sent for an MRI of the head, neck, chest, abdomen, and pelvis, which demonstrated 2 enlarged postauricular lymph nodes and raised suspicion for metastatic disease vs reactive lymphadenopathy. Mohs micrographic surgery with frozen sections was performed with 1- to 3-mm margins; the final layer was sent for permanent processing and confirmed negative margins. Sentinel lymph node biopsy and lymphadenectomy of the 2 nodes present on imaging showed no evidence of metastasis. The patient had no recurrence in 1 month.

Comment

Endocrine mucin-producing sweat gland carcinoma and PCMC are sweat gland malignancies that carry low metastatic potential but are locally aggressive. Endocrine mucin-producing sweat gland carcinoma has a strong predilection for the periorbital region, especially the lower eyelids of older women.³ Primary cutaneous mucinous carcinoma may arise on the eyelids, scalp, axillae, and trunk and has been reported more often in older men. These slow-growing tumors appear as nonspecific nodules.³ Lesions frequently are asymptomatic but rarely may cause pruritus and bleeding. Histologically, EMPSGC appears as solid or cystic nodules of cells with a papillary, cribriform, or pseudopapillary appearance. Intracellular or extracellular mucin as well as malignant spread of tumor cells along pre-existing ductlike structures make it difficult to histologically distinguish EMPSGC from ductal carcinoma in situ.³

A key histopathologic feature of PCMC is basophilic epithelioid cell nests in mucinous lakes.⁴ Rosettelike structures are seen within solid areas of the tumor. Fibrous septae separate individual collections of mucin, creating a lobulated appearance. The histopathologic differential diagnosis of EMPSGC and PCMC is broad, including basal cell carcinoma, hidradenoma, hidradenocarcinoma, apocrine adenoma, and dermal duct tumor. Positive expression of at least 1 neuroendocrine marker (ie, synaptophysin, neuron-specific enolase, chromogranin) and low-molecular cytokeratin (cytokeratin 7, CAM5.2, Ber-EP4) can aid in the diagnosis of both EMPSGC and PCMC.⁴ The use of p63 immunostaining is beneficial in delineating adnexal neoplasms. Adnexal tumors that stain positively with p63 are more likely to be of primary cutaneous origin, whereas lack of p63 staining usually denotes a secondary metastatic process. However, p63 staining is less reliable when distinguishing primary and metastatic mucinous neoplasms. Metastatic mucinous carcinomas often stain positive with p63, while PCMC usually stains negative despite its primary cutaneous origin, decreasing the clinical utility of p63. The tumor may be identical to metastatic mucinous adenocarcinoma of the breast, gastrointestinal tract, lung, ovary, and pancreas. Tumor islands floating in mucin are identified in both primary cutaneous and metastatic disease to the skin.^3,6 Areas of tumor necrosis, notable atypia, and perineural or lymphovascular invasion are infrequently reported in EMPSGC or PCMC, though lymphatic invasion was identified in case 5 presented herein.

A metastatic workup is warranted in all cases of PCMC, including a thorough history, review of systems, breast examination, and imaging. A workup may be considered in cases of EMPSGC depending on histologic features or clinical history.

There is uncertainty regarding the optimal management of these slow-growing yet locally destructive tumors.⁵ The incidence of local recurrence of PCMC after WLE with narrow margins of at least 1 cm can be as high as 30% to 40%, especially on the eyelid.⁴ There is no consensus on surgical care for either of these tumors.⁵ Because of the high recurrence rate and the predilection for the eyelid and face, MMS provides an excellent alternative to WLE for tissue preservation and meticulous margin control. We advocate for the use of the Mohs technique with permanent sectioning, which may delay the repair, but reviewing tissue with permanent fixation improves the quality and accuracy of the margin evaluation because these tumors often are infiltrative and difficult to delineate under frozen section processing. Permanent en face sectioning allows the laboratory to utilize the full array of immunohistochemical stains for these tumors, providing accurate and timely results.

Limitations to our retrospective uncontrolled study include missing or incomplete data points and short follow-up time. Additionally, there was no standardization to the margins removed with MMS or WLE because of the limited available data that comment on appropriate margins.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) and primary cutaneous mucinous carcinoma (PCMC) are rare low-grade neoplasms thought to arise from apocrine glands. These neoplasms share many histologic features and are proposed to be on a single histopathologic continuum, with EMPSGC as the in situ form that may progress to the invasive PCMC,¹ which is analogous to ductal carcinoma in situ and mucinous carcinoma of the breast, respectively.^2-5 Management involves a metastatic workup and either wide local excision (WLE) with margins greater than 5 mm or Mohs micrographic surgery (MMS) in anatomically sensitive areas.² We present 2 cases of EMPSGC and 3 cases of PCMC. We also review the clinical and histopathological features, differential diagnoses, and treatments.

Methods

Following institutional review board approval, we conducted a retrospective, single-institution case series. We searched electronic medical records dating from 2000 to 2019 for tumors diagnosed as PCMC or extramammary Paget disease treated with MMS. We gathered demographic, clinical, pathologic, and follow-up information from the electronic medical records for each case (Tables 1 and 2). Two dermatopathologists (B.P. and B.F.K.) reviewed the hematoxylin and eosin–stained slides of each tumor as well as all available immunohistochemical stains. One of the reviewers (B.F.K.) is a board-certified dermatologist, dermatopathologist, and fellowship-trained Mohs surgeon.

Results

Demographic and Clinical Information—We identified 2 cases of EMPSGC and 3 cases of PCMC diagnosed and treated at our institution; 4 of these cases had been treated within the last 2 years. One had been treated 18 years prior; case information was limited due to planned institutional record destruction. Three of the patients were female and 2 were male. The mean age at presentation was 71 years (range, 62–87 years). None had experienced recurrence or metastases after a mean follow-up of 30 months.

Case 1—A 68-year-old woman noted a slow-growing, flesh-colored papule measuring 12×10 mm on the right lower eyelid. An excisional biopsy was completed with 2-mm clinical margins, and the defect was closed in a linear fashion. Histologic sections demonstrated EMPSGC with uninvolved margins. The patient desired no further intervention and was clinically followed. Magnetic resonance imaging (MRI) of the head and neck found no evidence of metastasis. She has had no recurrence after 15 months.

Case 2—A 62-year-old man presented with a 7×5-mm, flesh-colored papule on the left lower eyelid margin (Figure 1). It was previously treated conservatively as a hordeolum but was biopsied after it failed to resolve with 3-mm margins. Histopathology demonstrated an EMPSGC (Figure 2). The lesion was treated with modified MMS with permanent en face section processing and cleared after 1 stage. Computed tomography of the head and neck showed no abnormalities. He has had no recurrence after 9 months.

Case 3—A 72-year-old man presented with a nontender papule near the right lateral canthus. A punch biopsy demonstrated PCMC. He was treated via modified MMS with permanent en face section processing. The tumor was cleared in 1 stage. He showed no evidence of recurrence after 112 months and died of unrelated causes. The rest of his clinical information was limited because of planned institutional destruction of records.

Case 4—An 87-year-old woman presented with a 25×25-mm, slow-growing mass of 12 months’ duration on the left lower abdomen (Figure 3). A biopsy demonstrated PCMC (Figure 4). Because of the size of the lesion, she underwent WLE with 20- to 30-mm margins by a general surgeon under general anesthesia. Positron emission tomography/computed tomography was unremarkable. She has remained disease free for 11 months.

Case 5—A 66-year-old woman presented for evaluation of a posterior scalp mass measuring 23×18 mm that had grown over the last 24 months. Biopsy showed mucinous carcinoma with lymphovascular invasion consistent with PCMC (Figure 5) confirmed on multiple tissue levels and with the aid of immunohistochemistry. She was sent for an MRI of the head, neck, chest, abdomen, and pelvis, which demonstrated 2 enlarged postauricular lymph nodes and raised suspicion for metastatic disease vs reactive lymphadenopathy. Mohs micrographic surgery with frozen sections was performed with 1- to 3-mm margins; the final layer was sent for permanent processing and confirmed negative margins. Sentinel lymph node biopsy and lymphadenectomy of the 2 nodes present on imaging showed no evidence of metastasis. The patient had no recurrence in 1 month.

Comment

Endocrine mucin-producing sweat gland carcinoma and PCMC are sweat gland malignancies that carry low metastatic potential but are locally aggressive. Endocrine mucin-producing sweat gland carcinoma has a strong predilection for the periorbital region, especially the lower eyelids of older women.³ Primary cutaneous mucinous carcinoma may arise on the eyelids, scalp, axillae, and trunk and has been reported more often in older men. These slow-growing tumors appear as nonspecific nodules.³ Lesions frequently are asymptomatic but rarely may cause pruritus and bleeding. Histologically, EMPSGC appears as solid or cystic nodules of cells with a papillary, cribriform, or pseudopapillary appearance. Intracellular or extracellular mucin as well as malignant spread of tumor cells along pre-existing ductlike structures make it difficult to histologically distinguish EMPSGC from ductal carcinoma in situ.³

A key histopathologic feature of PCMC is basophilic epithelioid cell nests in mucinous lakes.⁴ Rosettelike structures are seen within solid areas of the tumor. Fibrous septae separate individual collections of mucin, creating a lobulated appearance. The histopathologic differential diagnosis of EMPSGC and PCMC is broad, including basal cell carcinoma, hidradenoma, hidradenocarcinoma, apocrine adenoma, and dermal duct tumor. Positive expression of at least 1 neuroendocrine marker (ie, synaptophysin, neuron-specific enolase, chromogranin) and low-molecular cytokeratin (cytokeratin 7, CAM5.2, Ber-EP4) can aid in the diagnosis of both EMPSGC and PCMC.⁴ The use of p63 immunostaining is beneficial in delineating adnexal neoplasms. Adnexal tumors that stain positively with p63 are more likely to be of primary cutaneous origin, whereas lack of p63 staining usually denotes a secondary metastatic process. However, p63 staining is less reliable when distinguishing primary and metastatic mucinous neoplasms. Metastatic mucinous carcinomas often stain positive with p63, while PCMC usually stains negative despite its primary cutaneous origin, decreasing the clinical utility of p63. The tumor may be identical to metastatic mucinous adenocarcinoma of the breast, gastrointestinal tract, lung, ovary, and pancreas. Tumor islands floating in mucin are identified in both primary cutaneous and metastatic disease to the skin.^3,6 Areas of tumor necrosis, notable atypia, and perineural or lymphovascular invasion are infrequently reported in EMPSGC or PCMC, though lymphatic invasion was identified in case 5 presented herein.

A metastatic workup is warranted in all cases of PCMC, including a thorough history, review of systems, breast examination, and imaging. A workup may be considered in cases of EMPSGC depending on histologic features or clinical history.

There is uncertainty regarding the optimal management of these slow-growing yet locally destructive tumors.⁵ The incidence of local recurrence of PCMC after WLE with narrow margins of at least 1 cm can be as high as 30% to 40%, especially on the eyelid.⁴ There is no consensus on surgical care for either of these tumors.⁵ Because of the high recurrence rate and the predilection for the eyelid and face, MMS provides an excellent alternative to WLE for tissue preservation and meticulous margin control. We advocate for the use of the Mohs technique with permanent sectioning, which may delay the repair, but reviewing tissue with permanent fixation improves the quality and accuracy of the margin evaluation because these tumors often are infiltrative and difficult to delineate under frozen section processing. Permanent en face sectioning allows the laboratory to utilize the full array of immunohistochemical stains for these tumors, providing accurate and timely results.

Limitations to our retrospective uncontrolled study include missing or incomplete data points and short follow-up time. Additionally, there was no standardization to the margins removed with MMS or WLE because of the limited available data that comment on appropriate margins.

To the Editor:

Cat scratch disease (CSD) is caused by Bartonella henselae and Bartonella clarridgeiae bacteria transferred from cats to humans that results in an inflamed inoculation site and tender lymphadenopathy. Pityriasis rosea (PR) and PR-like eruptions are self-limited, acute exanthems that have been associated with infections, vaccinations, and medications. We report a case of PR occurring in a 10-year-old girl with CSD, which may suggest an association between the 2 diseases.

A 10-year-old girl who was otherwise healthy presented in the winter with a rash of 5 days’ duration. Fourteen days prior to the rash, the patient reported being scratched by a new kitten and noted a pinpoint “puncture” on the left forearm that developed into a red papule over the following week. Seven days after the cat scratch, the patient experienced pain and swelling in the left axilla. Approximately 1 week after the onset of lymphadenopathy, the patient developed an asymptomatic rash that started with a large spot on the left chest, followed by smaller spots appearing over the next 2 days and spreading to the rest of the trunk. Four days after the rash onset, the patient experienced a mild headache, low-grade subjective fever, and chills. She denied any recent travel, bug bites, sore throat, and diarrhea. She was up-to-date on all vaccinations and had not received any vaccines preceding the symptoms. Physical examination revealed a 2-cm pink, scaly, thin plaque with a collarette of scale on the left upper chest (herald patch), along with multiple thin pink papules and small plaques with central scale on the trunk (Figure 1). A pustule with adjacent linear erosion was present on the left ventral forearm (Figure 2). The patient had a tender subcutaneous nodule in the left axilla as well as bilateral anterior and posterior cervical-chain subcutaneous tender nodules. There was no involvement of the palms, soles, or mucosae.

The patient was empirically treated for CSD with azithromycin (200 mg/5 mL), 404 mg on day 1 followed by 202 mg daily for 4 days. The rash was treated with hydrocortisone cream 2.5% twice daily for 2 weeks. A wound culture of the pustule on the left forearm was negative for neutrophils and organisms. Antibody serologies obtained 4 weeks after presentation were notable for an elevated B henselae IgG titer of 1:640, confirming the diagnosis of CSD. Following treatment with azithromycin and hydrocortisone, all of the patient’s symptoms resolved after 1 to 2 weeks.

Cat scratch disease is a zoonotic infection caused by the bacteria B henselae and the more recently described pathogen B clarridgeiae. Cat fleas spread these bacteria among cats, which subsequently inoculate the bacteria into humans through bites and scratches. The incidence of CSD in the United States is estimated to be 4.5 to 9.3 per 100,000 individuals in the outpatient setting and 0.19 to 0.86 per 100,000 individuals in the inpatient setting.¹ Geographic variance can occur based on flea populations, resulting in higher incidence in warm humid climates and lower incidence in mountainous arid climates. The incidence of CSD in the pediatric population is highest in children aged 5 to 9 years. A national representative survey (N=3011) from 2017 revealed that 37.2% of primary care providers had diagnosed CSD in the prior year.¹

Classic CSD presents as an erythematous papule at the inoculation site lasting days to weeks, with progression to tender lymphadenopathy lasting weeks to months. Fever, malaise, and chills also can be seen. Atypical CSD occurs in up to 24% of cases in immunocompetent patients.¹ Atypical and systemic presentations are varied and can include fever of unknown origin, neuroretinitis, uveitis, retinal vessel occlusion, encephalitis, hepatosplenic lesions, Parinaud oculoglandular syndrome, osteomyelitis, and endocarditis.^1,2 Atypical dermatologic presentations of CSD include maculopapular rash in 7% of cases and erythema nodosum in 2.5% of cases, as well as rare reports of cutaneous vasculitis, urticaria, immune thrombocytopenic purpura, and papuloedematous eruption.³ Treatment guidelines for CSD vary widely depending on the clinical presentation as well as the immunocompetence of the infected individual. Our patient had limited regional lymphadenopathy with no signs of dissemination or neurologic involvement and was successfully treated with a 5-day course of oral azithromycin (weight based, 10 mg/kg). More extensive disease such as hepatosplenic or neurologic CSD may require multiple antibiotics for up to 6 weeks. Alternative or additional antibiotics used for CSD include rifampin, trimethoprim-sulfamethoxazole, ciprofloxacin, doxycycline, gentamicin, and clarithromycin. Opinions vary as to whether all patients or just those with complicated infections warrant antibiotic therapy.^4-6

Pityriasis rosea is a self-limited acute exanthematous disease that is classically associated with a systemic reactivation of human herpesvirus (HHV) 6 and/or HHV-7. The incidence of PR is estimated to be 480 per 100,000 dermatologic patients. It is slightly more common in females and occurs most often in patients aged 10 to 35 years.⁷ Clinically, PR appears with the abrupt onset of a single erythematous scaly patch (termed the herald patch), followed by a secondary eruption of smaller erythematous scaly macules and patches along the trunk’s cleavage lines. The secondary eruption on the back is sometimes termed a Christmas or fir tree pattern.^7,8

In addition to the classic presentation of PR, there have been reports of numerous atypical clinical presentations. The herald patch, which classically presents on the trunk, also has been reported to present on the extremities; PR of the extremities is defined by lesions that appear as large scaly plaques on the extremities only. Inverse PR presents with lesions occurring in flexural areas and acral surfaces but not on the trunk. There also is an acral PR variant in which lesions appear only on the palms, wrists, and soles. Purpuric or hemorrhagic PR has been described and presents with purpura and petechiae with or without collarettes of scale in diffuse locations, including the palate. Oral PR presents more commonly in patients of color as erosions, ulcers, hemorrhagic lesions, bullae, or geographic tongue. Erythema multiforme–like PR appears with targetoid lesions on the trunk, face, neck, and arms without a history of herpes simplex virus infection. A large pear-shaped herald patch has been reported and characterizes the gigantea PR of Darier variant. Irritated PR occurs with typical PR findings, but afflicted patients report severe pain and burning with diaphoresis. Relapsing PR can occur within 1 year of a prior episode of PR and presents without a herald patch. Persistent PR is defined by PR lasting more than 3 months, and most reported cases have included oral lesions. Finally, other PR variants that have been described include urticarial, papular, follicular, vesicular, and hypopigmented types.^7-9

Furthermore, there have been reports of multiple atypical presentations occurring simultaneously in the same patient.¹⁰ Although PR classically has been associated with HHV-6 and/or HHV-7 reactivation, it has been reported with a few other clinical situations and conditions. Pityriasislike eruption specifically refers to an exanthem secondary to drugs or vaccination that resembles PR but shows clinical differences, including diffuse and confluent dusky-red macules and/or plaques with or without desquamation on the trunk, extremities, and face. Drugs that have been implicated as triggers include ACE inhibitors, gold, isotretinoin, nonsteroidal anti-inflammatory agents, omeprazole, terbinafine, and tyrosine kinase inhibitors. Smallpox, tuberculosis, poliomyelitis, influenza, diphtheria, tetanus, hepatitis B virus, pneumococcus, papillomavirus, yellow fever, and pertussis vaccinations also have been associated with PR.^7,11,12 Additionally, PR has been reported to occur with active systemic infections, specifically H1N1 influenza, though it is rare.¹³ Because of its self-limited course, treatment of PR most often involves only reassurance. Topical corticosteroids may be appropriate for pruritus.^7,8

Pediatric health care providers including dermatologists should be familiar with both CSD and PR because they are common diseases that more often are encountered in the pediatric population. We present a unique case of CSD presenting with concurrent PR, which highlights a potential new etiology for PR and a rare cutaneous manifestation of CSD. Further investigation into a possible relationship between CSD and PR may be warranted. Patients with any signs and symptoms of fever, tender lymphadenopathy, worsening rash, or exposure to cats warrant a thorough history and physical examination to ensure that neither entity is overlooked.

To the Editor:

Cat scratch disease (CSD) is caused by Bartonella henselae and Bartonella clarridgeiae bacteria transferred from cats to humans that results in an inflamed inoculation site and tender lymphadenopathy. Pityriasis rosea (PR) and PR-like eruptions are self-limited, acute exanthems that have been associated with infections, vaccinations, and medications. We report a case of PR occurring in a 10-year-old girl with CSD, which may suggest an association between the 2 diseases.

A 10-year-old girl who was otherwise healthy presented in the winter with a rash of 5 days’ duration. Fourteen days prior to the rash, the patient reported being scratched by a new kitten and noted a pinpoint “puncture” on the left forearm that developed into a red papule over the following week. Seven days after the cat scratch, the patient experienced pain and swelling in the left axilla. Approximately 1 week after the onset of lymphadenopathy, the patient developed an asymptomatic rash that started with a large spot on the left chest, followed by smaller spots appearing over the next 2 days and spreading to the rest of the trunk. Four days after the rash onset, the patient experienced a mild headache, low-grade subjective fever, and chills. She denied any recent travel, bug bites, sore throat, and diarrhea. She was up-to-date on all vaccinations and had not received any vaccines preceding the symptoms. Physical examination revealed a 2-cm pink, scaly, thin plaque with a collarette of scale on the left upper chest (herald patch), along with multiple thin pink papules and small plaques with central scale on the trunk (Figure 1). A pustule with adjacent linear erosion was present on the left ventral forearm (Figure 2). The patient had a tender subcutaneous nodule in the left axilla as well as bilateral anterior and posterior cervical-chain subcutaneous tender nodules. There was no involvement of the palms, soles, or mucosae.

The patient was empirically treated for CSD with azithromycin (200 mg/5 mL), 404 mg on day 1 followed by 202 mg daily for 4 days. The rash was treated with hydrocortisone cream 2.5% twice daily for 2 weeks. A wound culture of the pustule on the left forearm was negative for neutrophils and organisms. Antibody serologies obtained 4 weeks after presentation were notable for an elevated B henselae IgG titer of 1:640, confirming the diagnosis of CSD. Following treatment with azithromycin and hydrocortisone, all of the patient’s symptoms resolved after 1 to 2 weeks.

Cat scratch disease is a zoonotic infection caused by the bacteria B henselae and the more recently described pathogen B clarridgeiae. Cat fleas spread these bacteria among cats, which subsequently inoculate the bacteria into humans through bites and scratches. The incidence of CSD in the United States is estimated to be 4.5 to 9.3 per 100,000 individuals in the outpatient setting and 0.19 to 0.86 per 100,000 individuals in the inpatient setting.¹ Geographic variance can occur based on flea populations, resulting in higher incidence in warm humid climates and lower incidence in mountainous arid climates. The incidence of CSD in the pediatric population is highest in children aged 5 to 9 years. A national representative survey (N=3011) from 2017 revealed that 37.2% of primary care providers had diagnosed CSD in the prior year.¹

Classic CSD presents as an erythematous papule at the inoculation site lasting days to weeks, with progression to tender lymphadenopathy lasting weeks to months. Fever, malaise, and chills also can be seen. Atypical CSD occurs in up to 24% of cases in immunocompetent patients.¹ Atypical and systemic presentations are varied and can include fever of unknown origin, neuroretinitis, uveitis, retinal vessel occlusion, encephalitis, hepatosplenic lesions, Parinaud oculoglandular syndrome, osteomyelitis, and endocarditis.^1,2 Atypical dermatologic presentations of CSD include maculopapular rash in 7% of cases and erythema nodosum in 2.5% of cases, as well as rare reports of cutaneous vasculitis, urticaria, immune thrombocytopenic purpura, and papuloedematous eruption.³ Treatment guidelines for CSD vary widely depending on the clinical presentation as well as the immunocompetence of the infected individual. Our patient had limited regional lymphadenopathy with no signs of dissemination or neurologic involvement and was successfully treated with a 5-day course of oral azithromycin (weight based, 10 mg/kg). More extensive disease such as hepatosplenic or neurologic CSD may require multiple antibiotics for up to 6 weeks. Alternative or additional antibiotics used for CSD include rifampin, trimethoprim-sulfamethoxazole, ciprofloxacin, doxycycline, gentamicin, and clarithromycin. Opinions vary as to whether all patients or just those with complicated infections warrant antibiotic therapy.^4-6

Pityriasis rosea is a self-limited acute exanthematous disease that is classically associated with a systemic reactivation of human herpesvirus (HHV) 6 and/or HHV-7. The incidence of PR is estimated to be 480 per 100,000 dermatologic patients. It is slightly more common in females and occurs most often in patients aged 10 to 35 years.⁷ Clinically, PR appears with the abrupt onset of a single erythematous scaly patch (termed the herald patch), followed by a secondary eruption of smaller erythematous scaly macules and patches along the trunk’s cleavage lines. The secondary eruption on the back is sometimes termed a Christmas or fir tree pattern.^7,8

In addition to the classic presentation of PR, there have been reports of numerous atypical clinical presentations. The herald patch, which classically presents on the trunk, also has been reported to present on the extremities; PR of the extremities is defined by lesions that appear as large scaly plaques on the extremities only. Inverse PR presents with lesions occurring in flexural areas and acral surfaces but not on the trunk. There also is an acral PR variant in which lesions appear only on the palms, wrists, and soles. Purpuric or hemorrhagic PR has been described and presents with purpura and petechiae with or without collarettes of scale in diffuse locations, including the palate. Oral PR presents more commonly in patients of color as erosions, ulcers, hemorrhagic lesions, bullae, or geographic tongue. Erythema multiforme–like PR appears with targetoid lesions on the trunk, face, neck, and arms without a history of herpes simplex virus infection. A large pear-shaped herald patch has been reported and characterizes the gigantea PR of Darier variant. Irritated PR occurs with typical PR findings, but afflicted patients report severe pain and burning with diaphoresis. Relapsing PR can occur within 1 year of a prior episode of PR and presents without a herald patch. Persistent PR is defined by PR lasting more than 3 months, and most reported cases have included oral lesions. Finally, other PR variants that have been described include urticarial, papular, follicular, vesicular, and hypopigmented types.^7-9

Furthermore, there have been reports of multiple atypical presentations occurring simultaneously in the same patient.¹⁰ Although PR classically has been associated with HHV-6 and/or HHV-7 reactivation, it has been reported with a few other clinical situations and conditions. Pityriasislike eruption specifically refers to an exanthem secondary to drugs or vaccination that resembles PR but shows clinical differences, including diffuse and confluent dusky-red macules and/or plaques with or without desquamation on the trunk, extremities, and face. Drugs that have been implicated as triggers include ACE inhibitors, gold, isotretinoin, nonsteroidal anti-inflammatory agents, omeprazole, terbinafine, and tyrosine kinase inhibitors. Smallpox, tuberculosis, poliomyelitis, influenza, diphtheria, tetanus, hepatitis B virus, pneumococcus, papillomavirus, yellow fever, and pertussis vaccinations also have been associated with PR.^7,11,12 Additionally, PR has been reported to occur with active systemic infections, specifically H1N1 influenza, though it is rare.¹³ Because of its self-limited course, treatment of PR most often involves only reassurance. Topical corticosteroids may be appropriate for pruritus.^7,8

Pediatric health care providers including dermatologists should be familiar with both CSD and PR because they are common diseases that more often are encountered in the pediatric population. We present a unique case of CSD presenting with concurrent PR, which highlights a potential new etiology for PR and a rare cutaneous manifestation of CSD. Further investigation into a possible relationship between CSD and PR may be warranted. Patients with any signs and symptoms of fever, tender lymphadenopathy, worsening rash, or exposure to cats warrant a thorough history and physical examination to ensure that neither entity is overlooked.

To the Editor:

Cat scratch disease (CSD) is caused by Bartonella henselae and Bartonella clarridgeiae bacteria transferred from cats to humans that results in an inflamed inoculation site and tender lymphadenopathy. Pityriasis rosea (PR) and PR-like eruptions are self-limited, acute exanthems that have been associated with infections, vaccinations, and medications. We report a case of PR occurring in a 10-year-old girl with CSD, which may suggest an association between the 2 diseases.

A 10-year-old girl who was otherwise healthy presented in the winter with a rash of 5 days’ duration. Fourteen days prior to the rash, the patient reported being scratched by a new kitten and noted a pinpoint “puncture” on the left forearm that developed into a red papule over the following week. Seven days after the cat scratch, the patient experienced pain and swelling in the left axilla. Approximately 1 week after the onset of lymphadenopathy, the patient developed an asymptomatic rash that started with a large spot on the left chest, followed by smaller spots appearing over the next 2 days and spreading to the rest of the trunk. Four days after the rash onset, the patient experienced a mild headache, low-grade subjective fever, and chills. She denied any recent travel, bug bites, sore throat, and diarrhea. She was up-to-date on all vaccinations and had not received any vaccines preceding the symptoms. Physical examination revealed a 2-cm pink, scaly, thin plaque with a collarette of scale on the left upper chest (herald patch), along with multiple thin pink papules and small plaques with central scale on the trunk (Figure 1). A pustule with adjacent linear erosion was present on the left ventral forearm (Figure 2). The patient had a tender subcutaneous nodule in the left axilla as well as bilateral anterior and posterior cervical-chain subcutaneous tender nodules. There was no involvement of the palms, soles, or mucosae.

The patient was empirically treated for CSD with azithromycin (200 mg/5 mL), 404 mg on day 1 followed by 202 mg daily for 4 days. The rash was treated with hydrocortisone cream 2.5% twice daily for 2 weeks. A wound culture of the pustule on the left forearm was negative for neutrophils and organisms. Antibody serologies obtained 4 weeks after presentation were notable for an elevated B henselae IgG titer of 1:640, confirming the diagnosis of CSD. Following treatment with azithromycin and hydrocortisone, all of the patient’s symptoms resolved after 1 to 2 weeks.

Cat scratch disease is a zoonotic infection caused by the bacteria B henselae and the more recently described pathogen B clarridgeiae. Cat fleas spread these bacteria among cats, which subsequently inoculate the bacteria into humans through bites and scratches. The incidence of CSD in the United States is estimated to be 4.5 to 9.3 per 100,000 individuals in the outpatient setting and 0.19 to 0.86 per 100,000 individuals in the inpatient setting.¹ Geographic variance can occur based on flea populations, resulting in higher incidence in warm humid climates and lower incidence in mountainous arid climates. The incidence of CSD in the pediatric population is highest in children aged 5 to 9 years. A national representative survey (N=3011) from 2017 revealed that 37.2% of primary care providers had diagnosed CSD in the prior year.¹

Classic CSD presents as an erythematous papule at the inoculation site lasting days to weeks, with progression to tender lymphadenopathy lasting weeks to months. Fever, malaise, and chills also can be seen. Atypical CSD occurs in up to 24% of cases in immunocompetent patients.¹ Atypical and systemic presentations are varied and can include fever of unknown origin, neuroretinitis, uveitis, retinal vessel occlusion, encephalitis, hepatosplenic lesions, Parinaud oculoglandular syndrome, osteomyelitis, and endocarditis.^1,2 Atypical dermatologic presentations of CSD include maculopapular rash in 7% of cases and erythema nodosum in 2.5% of cases, as well as rare reports of cutaneous vasculitis, urticaria, immune thrombocytopenic purpura, and papuloedematous eruption.³ Treatment guidelines for CSD vary widely depending on the clinical presentation as well as the immunocompetence of the infected individual. Our patient had limited regional lymphadenopathy with no signs of dissemination or neurologic involvement and was successfully treated with a 5-day course of oral azithromycin (weight based, 10 mg/kg). More extensive disease such as hepatosplenic or neurologic CSD may require multiple antibiotics for up to 6 weeks. Alternative or additional antibiotics used for CSD include rifampin, trimethoprim-sulfamethoxazole, ciprofloxacin, doxycycline, gentamicin, and clarithromycin. Opinions vary as to whether all patients or just those with complicated infections warrant antibiotic therapy.^4-6

Pityriasis rosea is a self-limited acute exanthematous disease that is classically associated with a systemic reactivation of human herpesvirus (HHV) 6 and/or HHV-7. The incidence of PR is estimated to be 480 per 100,000 dermatologic patients. It is slightly more common in females and occurs most often in patients aged 10 to 35 years.⁷ Clinically, PR appears with the abrupt onset of a single erythematous scaly patch (termed the herald patch), followed by a secondary eruption of smaller erythematous scaly macules and patches along the trunk’s cleavage lines. The secondary eruption on the back is sometimes termed a Christmas or fir tree pattern.^7,8

In addition to the classic presentation of PR, there have been reports of numerous atypical clinical presentations. The herald patch, which classically presents on the trunk, also has been reported to present on the extremities; PR of the extremities is defined by lesions that appear as large scaly plaques on the extremities only. Inverse PR presents with lesions occurring in flexural areas and acral surfaces but not on the trunk. There also is an acral PR variant in which lesions appear only on the palms, wrists, and soles. Purpuric or hemorrhagic PR has been described and presents with purpura and petechiae with or without collarettes of scale in diffuse locations, including the palate. Oral PR presents more commonly in patients of color as erosions, ulcers, hemorrhagic lesions, bullae, or geographic tongue. Erythema multiforme–like PR appears with targetoid lesions on the trunk, face, neck, and arms without a history of herpes simplex virus infection. A large pear-shaped herald patch has been reported and characterizes the gigantea PR of Darier variant. Irritated PR occurs with typical PR findings, but afflicted patients report severe pain and burning with diaphoresis. Relapsing PR can occur within 1 year of a prior episode of PR and presents without a herald patch. Persistent PR is defined by PR lasting more than 3 months, and most reported cases have included oral lesions. Finally, other PR variants that have been described include urticarial, papular, follicular, vesicular, and hypopigmented types.^7-9

Furthermore, there have been reports of multiple atypical presentations occurring simultaneously in the same patient.¹⁰ Although PR classically has been associated with HHV-6 and/or HHV-7 reactivation, it has been reported with a few other clinical situations and conditions. Pityriasislike eruption specifically refers to an exanthem secondary to drugs or vaccination that resembles PR but shows clinical differences, including diffuse and confluent dusky-red macules and/or plaques with or without desquamation on the trunk, extremities, and face. Drugs that have been implicated as triggers include ACE inhibitors, gold, isotretinoin, nonsteroidal anti-inflammatory agents, omeprazole, terbinafine, and tyrosine kinase inhibitors. Smallpox, tuberculosis, poliomyelitis, influenza, diphtheria, tetanus, hepatitis B virus, pneumococcus, papillomavirus, yellow fever, and pertussis vaccinations also have been associated with PR.^7,11,12 Additionally, PR has been reported to occur with active systemic infections, specifically H1N1 influenza, though it is rare.¹³ Because of its self-limited course, treatment of PR most often involves only reassurance. Topical corticosteroids may be appropriate for pruritus.^7,8

Pediatric health care providers including dermatologists should be familiar with both CSD and PR because they are common diseases that more often are encountered in the pediatric population. We present a unique case of CSD presenting with concurrent PR, which highlights a potential new etiology for PR and a rare cutaneous manifestation of CSD. Further investigation into a possible relationship between CSD and PR may be warranted. Patients with any signs and symptoms of fever, tender lymphadenopathy, worsening rash, or exposure to cats warrant a thorough history and physical examination to ensure that neither entity is overlooked.

The Diagnosis: Scabies Infestation

Direct microscopy revealed the presence of a live scabies mite and numerous eggs (Figure), confirming the diagnosis of a scabies infestation. Scabies, caused by the Sarcoptes scabiei var hominis mite, characteristically presents in adults as pruritic hyperkeratotic plaques of the interdigital web spaces of the hands, flexor surfaces of the wrists and elbows, axillae, male genitalia, and breasts; however, an atypical presentation is common in immunocompromised or immunosuppressed individuals, such as our patient. In children, the palms, soles, and head (ie, face, scalp, neck) are common sites of involvement. Although dermatologists generally are familiar with severe atypical presentations such as Norwegian crusted scabies or bullous scabies, it is important that they are aware of other atypical presentations, such as the diffuse papulonodular variant observed in our patient.¹ As such, a low threshold of suspicion for scabies infestations should be employed in immunocompromised patients with new-onset pruritic eruptions.

Direct microscopy is widely accepted as the gold standard for the diagnosis of scabies infestations; it is a fast and low-cost diagnostic tool. However, this technique displays variable sensitivity in clinical practice, requiring experience and a skilled hand.^1,2 Other more sensitive diagnostic options for suspected scabies infestations include histopathology, serology, and molecular-based techniques such as DNA isolation and polymerase chain reaction. Although these tests do demonstrate greater sensitivity, they also are more invasive, time intensive, and costly.² Therefore, they typically are not the first choice for a suspected scabies infestation. Dermoscopy has emerged as another tool to aid in the diagnosis of a suspected scabies infestation, enabling visualization of scaly burrows, eggs, and live mites. Classically, findings resembling a delta wing with contrail are seen on dermoscopic examination. The delta wing represents the brown triangular structure of the pigmented scabies mite head and anterior legs; the contrail is the lighter linear structures streaming behind the scabies mite (similar to visible vapor streams occurring behind flying jets), representing the burrow of the mite.

Although treatment of scabies infestations typically can be accomplished with permethrin cream 5%, the diffuse nature of our patient’s lesions in combination with his immunocompromised state made oral therapy a more appropriate choice. Based on Centers for Disease Control and Prevention recommendations, the patient received 2 doses of oral weight-based ivermectin (200 μg/kg per dose) administered 1 week apart.^1,3 The initial dose at day 1 serves to eliminate any scabies mites that are present, while the second dose 1 week later eliminates any residual eggs. Our patient experienced complete resolution of the symptoms following this treatment regimen.

It was important to differentiate our patient’s scabies infestation from other intensely pruritic conditions and morphologic mimics including papular urticaria, lichenoid drug eruptions, tinea corporis, and prurigo nodularis. Papular urticaria is an intensely pruritic hypersensitivity reaction to insect bites that commonly affects the extremities or other exposed areas. Visible puncta may be present.⁴ Our patient’s lesion distribution involved areas covered by clothing, no puncta were present, and he had no history of a recent arthropod assault, making the diagnosis of papular urticaria less likely.

Lichenoid drug eruptions classically present with symmetric, diffuse, pruritic, violaceous, scaling papules and plaques that present 2 to 3 months after exposure to an offending agent.⁵ Our patient’s eruption was papulonodular with no violaceous plaques, and he did not report changes to his medications, making a lichenoid drug eruption less likely.

Tinea corporis is another intensely pruritic condition that should be considered, especially in immunocompromised patients. It is caused by dermatophytes and classically presents as erythematous pruritic plaques with an annular, advancing, scaling border.⁶ Although immunocompromised patients may display extensive involvement, our patient’s lesions were papulonodular with no annular morphology or scale, rendering tinea corporis less likely.

Prurigo nodularis is a chronic condition characterized by pruritic, violaceous, dome-shaped, smooth or crusted nodules secondary to repeated scratching or pressure. Although prurigo nodules can develop as a secondary change due to chronic excoriations in scabies infestations, prurigo nodules usually do not develop in areas such as the midline of the back that are not easily reached by the fingernails,⁷ which made prurigo nodularis less likely in our patient.

This case describes a unique papulonodular variant of scabies presenting in an immunocompromised cancer patient. Timely recognition and diagnosis of atypical scabies infestations can decrease morbidity and improve the quality of life of these patients.

The Diagnosis: Scabies Infestation

Direct microscopy revealed the presence of a live scabies mite and numerous eggs (Figure), confirming the diagnosis of a scabies infestation. Scabies, caused by the Sarcoptes scabiei var hominis mite, characteristically presents in adults as pruritic hyperkeratotic plaques of the interdigital web spaces of the hands, flexor surfaces of the wrists and elbows, axillae, male genitalia, and breasts; however, an atypical presentation is common in immunocompromised or immunosuppressed individuals, such as our patient. In children, the palms, soles, and head (ie, face, scalp, neck) are common sites of involvement. Although dermatologists generally are familiar with severe atypical presentations such as Norwegian crusted scabies or bullous scabies, it is important that they are aware of other atypical presentations, such as the diffuse papulonodular variant observed in our patient.¹ As such, a low threshold of suspicion for scabies infestations should be employed in immunocompromised patients with new-onset pruritic eruptions.

Direct microscopy is widely accepted as the gold standard for the diagnosis of scabies infestations; it is a fast and low-cost diagnostic tool. However, this technique displays variable sensitivity in clinical practice, requiring experience and a skilled hand.^1,2 Other more sensitive diagnostic options for suspected scabies infestations include histopathology, serology, and molecular-based techniques such as DNA isolation and polymerase chain reaction. Although these tests do demonstrate greater sensitivity, they also are more invasive, time intensive, and costly.² Therefore, they typically are not the first choice for a suspected scabies infestation. Dermoscopy has emerged as another tool to aid in the diagnosis of a suspected scabies infestation, enabling visualization of scaly burrows, eggs, and live mites. Classically, findings resembling a delta wing with contrail are seen on dermoscopic examination. The delta wing represents the brown triangular structure of the pigmented scabies mite head and anterior legs; the contrail is the lighter linear structures streaming behind the scabies mite (similar to visible vapor streams occurring behind flying jets), representing the burrow of the mite.

Although treatment of scabies infestations typically can be accomplished with permethrin cream 5%, the diffuse nature of our patient’s lesions in combination with his immunocompromised state made oral therapy a more appropriate choice. Based on Centers for Disease Control and Prevention recommendations, the patient received 2 doses of oral weight-based ivermectin (200 μg/kg per dose) administered 1 week apart.^1,3 The initial dose at day 1 serves to eliminate any scabies mites that are present, while the second dose 1 week later eliminates any residual eggs. Our patient experienced complete resolution of the symptoms following this treatment regimen.

It was important to differentiate our patient’s scabies infestation from other intensely pruritic conditions and morphologic mimics including papular urticaria, lichenoid drug eruptions, tinea corporis, and prurigo nodularis. Papular urticaria is an intensely pruritic hypersensitivity reaction to insect bites that commonly affects the extremities or other exposed areas. Visible puncta may be present.⁴ Our patient’s lesion distribution involved areas covered by clothing, no puncta were present, and he had no history of a recent arthropod assault, making the diagnosis of papular urticaria less likely.

Lichenoid drug eruptions classically present with symmetric, diffuse, pruritic, violaceous, scaling papules and plaques that present 2 to 3 months after exposure to an offending agent.⁵ Our patient’s eruption was papulonodular with no violaceous plaques, and he did not report changes to his medications, making a lichenoid drug eruption less likely.

Tinea corporis is another intensely pruritic condition that should be considered, especially in immunocompromised patients. It is caused by dermatophytes and classically presents as erythematous pruritic plaques with an annular, advancing, scaling border.⁶ Although immunocompromised patients may display extensive involvement, our patient’s lesions were papulonodular with no annular morphology or scale, rendering tinea corporis less likely.

Prurigo nodularis is a chronic condition characterized by pruritic, violaceous, dome-shaped, smooth or crusted nodules secondary to repeated scratching or pressure. Although prurigo nodules can develop as a secondary change due to chronic excoriations in scabies infestations, prurigo nodules usually do not develop in areas such as the midline of the back that are not easily reached by the fingernails,⁷ which made prurigo nodularis less likely in our patient.

This case describes a unique papulonodular variant of scabies presenting in an immunocompromised cancer patient. Timely recognition and diagnosis of atypical scabies infestations can decrease morbidity and improve the quality of life of these patients.

The Diagnosis: Scabies Infestation

Direct microscopy revealed the presence of a live scabies mite and numerous eggs (Figure), confirming the diagnosis of a scabies infestation. Scabies, caused by the Sarcoptes scabiei var hominis mite, characteristically presents in adults as pruritic hyperkeratotic plaques of the interdigital web spaces of the hands, flexor surfaces of the wrists and elbows, axillae, male genitalia, and breasts; however, an atypical presentation is common in immunocompromised or immunosuppressed individuals, such as our patient. In children, the palms, soles, and head (ie, face, scalp, neck) are common sites of involvement. Although dermatologists generally are familiar with severe atypical presentations such as Norwegian crusted scabies or bullous scabies, it is important that they are aware of other atypical presentations, such as the diffuse papulonodular variant observed in our patient.¹ As such, a low threshold of suspicion for scabies infestations should be employed in immunocompromised patients with new-onset pruritic eruptions.

Direct microscopy is widely accepted as the gold standard for the diagnosis of scabies infestations; it is a fast and low-cost diagnostic tool. However, this technique displays variable sensitivity in clinical practice, requiring experience and a skilled hand.^1,2 Other more sensitive diagnostic options for suspected scabies infestations include histopathology, serology, and molecular-based techniques such as DNA isolation and polymerase chain reaction. Although these tests do demonstrate greater sensitivity, they also are more invasive, time intensive, and costly.² Therefore, they typically are not the first choice for a suspected scabies infestation. Dermoscopy has emerged as another tool to aid in the diagnosis of a suspected scabies infestation, enabling visualization of scaly burrows, eggs, and live mites. Classically, findings resembling a delta wing with contrail are seen on dermoscopic examination. The delta wing represents the brown triangular structure of the pigmented scabies mite head and anterior legs; the contrail is the lighter linear structures streaming behind the scabies mite (similar to visible vapor streams occurring behind flying jets), representing the burrow of the mite.

Although treatment of scabies infestations typically can be accomplished with permethrin cream 5%, the diffuse nature of our patient’s lesions in combination with his immunocompromised state made oral therapy a more appropriate choice. Based on Centers for Disease Control and Prevention recommendations, the patient received 2 doses of oral weight-based ivermectin (200 μg/kg per dose) administered 1 week apart.^1,3 The initial dose at day 1 serves to eliminate any scabies mites that are present, while the second dose 1 week later eliminates any residual eggs. Our patient experienced complete resolution of the symptoms following this treatment regimen.

It was important to differentiate our patient’s scabies infestation from other intensely pruritic conditions and morphologic mimics including papular urticaria, lichenoid drug eruptions, tinea corporis, and prurigo nodularis. Papular urticaria is an intensely pruritic hypersensitivity reaction to insect bites that commonly affects the extremities or other exposed areas. Visible puncta may be present.⁴ Our patient’s lesion distribution involved areas covered by clothing, no puncta were present, and he had no history of a recent arthropod assault, making the diagnosis of papular urticaria less likely.

Lichenoid drug eruptions classically present with symmetric, diffuse, pruritic, violaceous, scaling papules and plaques that present 2 to 3 months after exposure to an offending agent.⁵ Our patient’s eruption was papulonodular with no violaceous plaques, and he did not report changes to his medications, making a lichenoid drug eruption less likely.

Tinea corporis is another intensely pruritic condition that should be considered, especially in immunocompromised patients. It is caused by dermatophytes and classically presents as erythematous pruritic plaques with an annular, advancing, scaling border.⁶ Although immunocompromised patients may display extensive involvement, our patient’s lesions were papulonodular with no annular morphology or scale, rendering tinea corporis less likely.

Prurigo nodularis is a chronic condition characterized by pruritic, violaceous, dome-shaped, smooth or crusted nodules secondary to repeated scratching or pressure. Although prurigo nodules can develop as a secondary change due to chronic excoriations in scabies infestations, prurigo nodules usually do not develop in areas such as the midline of the back that are not easily reached by the fingernails,⁷ which made prurigo nodularis less likely in our patient.

This case describes a unique papulonodular variant of scabies presenting in an immunocompromised cancer patient. Timely recognition and diagnosis of atypical scabies infestations can decrease morbidity and improve the quality of life of these patients.

The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin

A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.

The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,¹ who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.¹ Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.^2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.

Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.⁴ In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.⁵ Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.⁶ Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.⁴

Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.

The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin

A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.

The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,¹ who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.¹ Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.^2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.

Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.⁴ In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.⁵ Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.⁶ Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.⁴

Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.

The Diagnosis: Infantile Transient Smooth Muscle Contraction of the Skin

A diagnosis of infantile transient smooth muscle contraction of the skin (ITSMC) was made based on our patient’s clinical presentation and eliminating the diagnoses in the differential. No treatment ultimately was indicated, as episodes became less frequent over time.

The term infantile transient smooth muscle contraction of the skin was first proposed in 2013 by Torrelo et al,¹ who described 9 newborns with episodic skin rippling occasionally associated with exposure to cold or friction. The authors postulated that ITSMC was the result of a transient contraction of the arrector pili smooth muscle fibers of the skin, secondary to autonomic immaturity, primitive reflexes, or smooth muscle hypersensitivity.¹ Since this first description, ITSMC has remained a rarely reported and poorly understood phenomenon with rare identified cases in the literature.^2,3 Clinical history and examination of infants with intermittent transient skin rippling help to distinguish ITSMC from other diagnoses without the need for biopsy, which is particularly undesirable in the pediatric population.

Congenital smooth muscle hamartoma is a benign proliferation of mature smooth muscle that also can arise from the arrector pili muscles.⁴ In contrast to ITSMC, a hamartoma does not clear; rather, it persists and grows proportionally with the child and is associated with overlying hyperpigmentation and hypertrichosis. The transient nature of ITSMC may be worrisome for mastocytoma; however, this condition presents as erythematous, yellow, red, or brown macules, papules, plaques, or nodules with a positive Darier sign.⁵ Although the differential diagnosis includes the shagreen patch characteristic of tuberous sclerosis, this irregular plaque typically is located on the lower back with overlying peau d’orange skin changes, and our patient lacked other features indicative of this condition.⁶ Becker nevus also remains a consideration in patients with rippled skin, but this entity typically becomes more notable at puberty and is associated with hyperpigmentation and hypertrichosis and is a type of smooth muscle hamartoma.⁴

Our case highlighted the unusual presentation of ITSMC, a condition that can easily go unrecognized, leading to unnecessary referrals and concern. Familiarity with this benign diagnosis is essential to inform prognosis and guide management.

In the United States, acne affects 85% of adolescents and can persist into adulthood at a prevalence of 30% to 50% in adult women. ^1,2 The pathogenesis of acne is multifactorial and involves hyperkeratinization of the follicle, bacterial colonization with Cutibacterium acnes , and increased androgen-induced sebum production, which together lead to inflammation. ^3,4 A wide range of treatment guideline–recommended options are available, including benzoyl peroxide (BPO), topical retinoids, topical and oral antibiotics, antiandrogens, and isotretinoin. ⁵ However, these options vary widely in their clinical uses, effectiveness, and costs.

Why Cost-effective Acne Care Matters

Out-of-pocket spending by patients on acne treatments can be substantial, with surveys finding that acne patients often spend hundreds to thousands of dollars per year.^6,7 In a poll conducted in 2019 by the Kaiser Family Foundation, 3 in 10 patients said they had not taken their medicine as prescribed because of costs.⁸ A mixed methods study by Ryskina et al⁹ found that 65% (17/26) of participants who reported primary nonadherence—intended to fill prescriptions but were unable to do so—cited cost or coverage-related barriers as the reason. With the continued rise of dermatologic drug prices and increased prevalence of high-deductible health plans, cost-effective treatment continues to grow in importance. Failure to consider cost-effective, patient-centered care may lead to increased financial toxicity, reduced adherence, and ultimately worse outcomes and patient satisfaction. We aim to review the cost-effectiveness of current prescription therapies for acne management and highlight the most cost-effective approaches to patients with mild to moderate acne as well as moderate to severe acne.

In this review, we will take a value-oriented framework.¹⁰ Value can be defined as the cost per outcome of interest. Therefore, a treatment does not necessarily need to be inexpensive to provide high value if it delivers outstanding clinical outcomes. In addition, we will focus on incremental cost-effectiveness relative to common alternatives (eg, a retinoid could deliver high value relative to a vehicle but still provide limited value compared to other available retinoids if it is more expensive but not more efficacious). When possible, we present data from cost-effectiveness studies.^11,12 We also use recent available price data obtained from GoodRx on August 11, 2023, to guide this discussion.¹³ However, as comparative-effectiveness and cost-effectiveness studies rarely are performed for acne medications, much of this discussion will be based on expert opinion.

Treatment Categories

Topical Retinoids—There currently are 4 topical retinoids that are approved by the US Food and Drug Administration (FDA) for the treatment of acne: tretinoin, tazarotene, trifarotene, and adapalene. These drugs are vitamin A derivatives that bind retinoic acid receptors and function as comedolytic and anti-inflammatory agents.⁵ In general, generic tretinoin and adapalene products have the lowest cost (Table).

In network meta-analyses, tretinoin and adapalene often are highly ranked topical treatment options with respect to efficacy.¹⁴ Combined with their low cost, generic tretinoin and adapalene likely are excellent initial options for topical therapy from the standpoint of cost-effectiveness.¹⁵ Adapalene may be preferred in many situations because of its better photostability and compatibility with BPO.

Due to the importance of the vehicle in determining retinoid tolerability, efforts have been made to use encapsulation and polymeric emulsion technology to improve tolerability. Recently, polymeric lotion formulations of tretinoin and tazarotene have become available. In a phase 2 study, tazarotene lotion 0.045% was found to have equivalent efficacy and superior tolerability to tazarotene cream 0.1%.¹⁶ Although head-to-head data are not available, it is likely that tretinoin lotion may offer similar tolerability improvements.¹⁷ Although these formulations currently are more costly, this improved tolerability may be critical for some patients to be able to use topical retinoids, and the additional cost may be worthwhile. In addition, as these products lose market exclusivity, they may become more affordable and similarly priced to other topical retinoids. It is important to keep in mind that in clinical trials of tretinoin and adapalene, rates of dropout due to adverse events typically were 1% to 2%; therefore, because many patients can tolerate generic tretinoin and adapalene, at current prices the lotion formulations of retinoids may not be cost-effective relative to these generics.¹⁴

Trifarotene cream 0.005%, a fourth-generation topical retinoid that is highly sensitive for retinoic acid receptor γ, recently was FDA approved for the treatment of acne. Although trifarotene is efficacious for both facial and truncal acne, there is a lack of active comparator data compared to other topical retinoids.¹⁸ In a 2023 network meta-analysis, trifarotene was found to be both less efficacious and less tolerable compared to other topical retinoids.¹⁹ Thus, it is unclear if trifarotene offers any improved efficacy compared to other options, and it comes at a much higher cost (Table). In a tolerability study, trifarotene was found to be significantly more irritating than tazarotene lotion 0.045% and adapalene gel 0.3% (P<.05).²⁰ Therefore, trifarotene cream 0.005% is unlikely to be a cost-effective option; in fact, it may be overall inferior to other topical retinoids, given its potentially lower tolerability.

Topical Antibiotics—There are 4 commonly prescribed topical antibiotics that are approved by the FDA for the treatment of acne: clindamycin, erythromycin, dapsone, and minocycline. The American Academy of Dermatology guidelines for the treatment of acne recommend concomitant use of BPO to prevent antibiotic resistance.⁵ Clindamycin is favored over erythromycin because of increasing antibiotic resistance to erythromycin.²¹ Inexpensive generic options in multiple vehicles (eg, solution, foam, gel) make clindamycin a highly cost-effective option when antibiotic therapy is desired as part of a topical regimen (Table).

The cost-effectiveness of dapsone gel and minocycline foam relative to clindamycin are less certain. Rates of resistance to minocycline are lower than clindamycin, and minocycline foam may be a reasonable alternative in patients who have not had success with other topical antibiotics, such as clindamycin.²² However, given the absence of comparative effectiveness data to suggest minocycline is more effective than clindamycin, it is difficult to justify the substantially higher cost for the typical patient. Although dapsone gel has been suggested as an option for adult women with acne, there are no data to support that it is any more effective than other topical antibiotics in this patient population.²³ As generic dapsone prices decrease, it may become a reasonable alternative to clindamycin. In addition, the antineutrophil properties of dapsone may be useful in other acneform and inflammatory eruptions, such as scalp folliculitis and folliculitis decalvans.²⁴

Combination Topicals—Current combination topical products include antibiotic and BPO, antibiotic and retinoid, and retinoid and BPO. Use of combination agents is recommended to reduce the risk for resistance and to enhance effectiveness. Combination products offer improved convenience, which is associated with better adherence and outcomes.²⁵ Generic fixed-dose adapalene-BPO can be a highly cost-effective option that can sometimes be less expensive than the individual component products (Table). Similarly, fixed-dose clindamycin-BPO also is likely to be highly cost-effective. A network meta-analysis found fixed-dose adapalene-BPO to be the most efficacious topical treatment, though it also was found to be the most irritating—more so than fixed-dose clindamycin-BPO, which may have similar efficacy.^14,26,27 Generic fixed-dose tretinoin-clindamycin offers improved convenience and adherence compared to the individual components, but it is more expensive, and its cost-effectiveness may be influenced by the importance of convenience for the patient.²⁵ An encapsulated, fixed-dose tretinoin 0.1%–BPO 3% cream is FDA approved for acne, but the cost is high and there is a lack of comparative effectiveness data demonstrating advantages over generic fixed-dose adapalene-BPO products.

Topical Antiandrogen—Clascoterone was introduced in 2020 as the first FDA-approved topical medication to target the hormonal pathogenesis of acne, inhibiting the androgen receptors in the sebaceous gland.²⁸ Because it is rapidly metabolized to cortexolone and does not have systemic antiandrogen effects, clascoterone can be used in both men and women with acne. In clinical trials, it had minimal side effects, including no evidence of irritability, which is an advantage over topical retinoids and BPO.²⁹ In addition, a phase 2 study found that clascoterone may have similar to superior efficacy to tretinoin cream 0.05%.³⁰ Although clascoterone has several strengths, including its efficacy, tolerability, and unique mechanism of action, its cost-effectiveness is limited due to its high cost (Table) and the need for twice-daily application, which reduces convenience. Clascoterone likely is best reserved for patients with a strong hormonal pathogenesis of their acne or difficulty tolerating other topicals, or as an additional therapy to complement other topicals.

Oral Antibiotics—Oral antibiotics are the most commonly prescribed systemic treatments for acne, particularly tetracyclines such as doxycycline, minocycline, and sarecycline.^31-34 Doxycycline and minocycline are considered first-line oral antibiotic therapy in the United States and are inexpensive and easily accessible.⁵ Doxycycline generally is recommended over minocycline given lack of evidence of superior efficacy of minocycline and concerns about severe adverse cutaneous reactions and drug-induced lupus with minocycline.³⁵

In recent years, there has been growing concern of the development of antibiotic resistance.⁵ Sarecycline is a narrow-spectrum tetracycline that was FDA approved for acne in 2018. In vitro studies demonstrate sarecycline maintains high efficacy against C acnes with less activity against other bacteria, particularly gram-negative enterobes.³⁶ The selectivity of sarecycline may lessen alterations of the gut microbiome seen with other oral antibiotics and reduce gastrointestinal tract side effects. Although comparative effectiveness studies are lacking, sarecycline was efficacious in phase 3 trials with few side effects compared with placebo.³⁷ However, at this time, given the absence of comparative effectiveness data and its high cost (Table), sarecycline likely is best reserved for patients with comorbidities (eg, gastrointestinal disease), those requiring long-term antibiotic therapy, or those with acne that has failed to respond to other oral antibiotics.

Hormonal Treatments—Hormonal treatments such as combined oral contraceptives (COCs) and spironolactone often are considered second-line options, though they may represent cost-effective and safe alternatives to oral antibiotics for women with moderate to severe acne.^38-41 There currently are 4 COCs approved by the FDA for the treatment of moderate acne in postmenarcheal females: drospirenone-ethinyl estradiol (Yaz [Bayer HealthCare Pharmaceuticals, Inc]), ethinyl estradiol-norgestimate (Ortho Tri-Cyclen [Ortho-McNeil Pharmaceuticals, Inc]), drospirenone-ethinyl estradiol-levomefolate (Beyaz [Bayer HealthCare Pharmaceuticals, Inc]), and ethinyl estradiol-norethindrone acetate-ferrous fumarate (Estrostep Fe [Allergan USA, Inc]).⁵ Treatment with COCs has been shown to cause substantial reductions in lesion counts across all lesion types compared to placebo, and a meta-analysis of 24 randomized trials conducted by Arowojolu et al⁴² demonstrated no consistent differences in acne reduction among different COCs.^43,44 Although oral antibiotics are associated with faster improvement than COCs, there is some evidence that they have similar efficacy at 6 months of therapy.⁴⁵ Combined oral contraceptives are inexpensive and likely reflect a highly cost-effective option (Table).

Spironolactone is an aldosterone inhibitor and androgen receptor blocker that is used off label to treat acne. It is one of the least expensive systemic medications for acne (Table). Although randomized controlled trials are lacking, several large case series support the effectiveness of spironolactone for women with acne.^38,46 In addition, observational data suggest spironolactone may have similar effectiveness to oral antibiotics.⁴¹ Spironolactone generally is well tolerated, with the most common adverse effects being menstrual irregularities, breast tenderness, and diuresis.^47,48 Many of these adverse effects are dose dependent and less likely with the dosing used in acne care. Additionally, menstrual irregularities can be reduced by concomitant use of a COC.⁴⁸

Although frequent potassium monitoring remains common among patients being treated with spironolactone, there is growing evidence to suggest that potassium monitoring is of low value in young healthy women with acne.^49-51 Reducing this laboratory monitoring likely represents an opportunity to provide higher-value care to patients being treated with spironolactone. However, laboratory monitoring should be considered if risk factors for hyperkalemia are present (eg, older age, comorbidities, medications).⁵¹

Isotretinoin—Isotretinoin is the most efficacious treatment available for acne and has the unique property of being able to induce a remission of acne activity for many patients.⁵ Although it remains modestly expensive (Table), it may be less costly overall relative to other treatments that may need continued use over many years because it can induce a remission of acne activity. As with spironolactone, frequent laboratory monitoring remains common among patients being treated with isotretinoin. There is no evidence to support checking complete blood cell counts.⁵² Several observational studies and a Delphi consensus support reduced monitoring, such as checking lipids and alanine aminotransferase at baseline and peak dose in otherwise young healthy patients.^53,54 A recent critically appraised topic published in the British Journal of Dermatology has proposed eliminating laboratory monitoring entirely.⁵⁵ Reducing laboratory monitoring for patients being treated with isotretinoin has been estimated to potentially save $100 million to $200 million per year in the United States.^52-54

Other Strategies to Reduce Patient Costs

Although choosing a cost-effective treatment approach is critical to preventing financial toxicity given poor coverage for acne care and the growth of high-deductible insurance plans, some patients may still experience high treatment costs.⁵⁶ Because pharmacy costs often are inflated, potentially related to practices of pharmacy benefit managers, it often is possible to find better prices than the presented list price, either by using platforms such as GoodRx or through direct-to-patient mail-order pharmacies such as Cost Plus Drug.⁵⁷ For branded medications, some patients may be eligible for patient-assistance programs, though they typically are not available for those with public insurance such as Medicare or Medicaid. Compounding pharmacies offer another approach to reduce cost and improve convenience for patients, but because the vehicle can influence the efficacy and tolerability of some topical medications, it is possible that these compounded formulations may not perform similarly to the original FDA-approved products.

Conclusion

For mild to moderate acne, multimodal topical therapy often is required. Fixed-dose combination adapalene-BPO and clindamycin-BPO are highly cost-effective options for most patients. Lotion formulations of topical retinoids may be useful in patients with difficulty tolerating other formulations. Clascoterone is a novel topical antiandrogen that is more expensive than other topical therapies but can complement other topical therapies and is well tolerated.

For moderate to severe acne, doxycycline or hormonal therapy (ie, COCs, spironolactone) are highly cost-effective options. Isotretinoin is recommended for severe or scarring acne. Reduced laboratory monitoring for spironolactone and isotretinoin is an opportunity to provide higher-value care.

In the United States, acne affects 85% of adolescents and can persist into adulthood at a prevalence of 30% to 50% in adult women. ^1,2 The pathogenesis of acne is multifactorial and involves hyperkeratinization of the follicle, bacterial colonization with Cutibacterium acnes , and increased androgen-induced sebum production, which together lead to inflammation. ^3,4 A wide range of treatment guideline–recommended options are available, including benzoyl peroxide (BPO), topical retinoids, topical and oral antibiotics, antiandrogens, and isotretinoin. ⁵ However, these options vary widely in their clinical uses, effectiveness, and costs.

Why Cost-effective Acne Care Matters

Out-of-pocket spending by patients on acne treatments can be substantial, with surveys finding that acne patients often spend hundreds to thousands of dollars per year.^6,7 In a poll conducted in 2019 by the Kaiser Family Foundation, 3 in 10 patients said they had not taken their medicine as prescribed because of costs.⁸ A mixed methods study by Ryskina et al⁹ found that 65% (17/26) of participants who reported primary nonadherence—intended to fill prescriptions but were unable to do so—cited cost or coverage-related barriers as the reason. With the continued rise of dermatologic drug prices and increased prevalence of high-deductible health plans, cost-effective treatment continues to grow in importance. Failure to consider cost-effective, patient-centered care may lead to increased financial toxicity, reduced adherence, and ultimately worse outcomes and patient satisfaction. We aim to review the cost-effectiveness of current prescription therapies for acne management and highlight the most cost-effective approaches to patients with mild to moderate acne as well as moderate to severe acne.

In this review, we will take a value-oriented framework.¹⁰ Value can be defined as the cost per outcome of interest. Therefore, a treatment does not necessarily need to be inexpensive to provide high value if it delivers outstanding clinical outcomes. In addition, we will focus on incremental cost-effectiveness relative to common alternatives (eg, a retinoid could deliver high value relative to a vehicle but still provide limited value compared to other available retinoids if it is more expensive but not more efficacious). When possible, we present data from cost-effectiveness studies.^11,12 We also use recent available price data obtained from GoodRx on August 11, 2023, to guide this discussion.¹³ However, as comparative-effectiveness and cost-effectiveness studies rarely are performed for acne medications, much of this discussion will be based on expert opinion.

Treatment Categories

Topical Retinoids—There currently are 4 topical retinoids that are approved by the US Food and Drug Administration (FDA) for the treatment of acne: tretinoin, tazarotene, trifarotene, and adapalene. These drugs are vitamin A derivatives that bind retinoic acid receptors and function as comedolytic and anti-inflammatory agents.⁵ In general, generic tretinoin and adapalene products have the lowest cost (Table).

In network meta-analyses, tretinoin and adapalene often are highly ranked topical treatment options with respect to efficacy.¹⁴ Combined with their low cost, generic tretinoin and adapalene likely are excellent initial options for topical therapy from the standpoint of cost-effectiveness.¹⁵ Adapalene may be preferred in many situations because of its better photostability and compatibility with BPO.

Due to the importance of the vehicle in determining retinoid tolerability, efforts have been made to use encapsulation and polymeric emulsion technology to improve tolerability. Recently, polymeric lotion formulations of tretinoin and tazarotene have become available. In a phase 2 study, tazarotene lotion 0.045% was found to have equivalent efficacy and superior tolerability to tazarotene cream 0.1%.¹⁶ Although head-to-head data are not available, it is likely that tretinoin lotion may offer similar tolerability improvements.¹⁷ Although these formulations currently are more costly, this improved tolerability may be critical for some patients to be able to use topical retinoids, and the additional cost may be worthwhile. In addition, as these products lose market exclusivity, they may become more affordable and similarly priced to other topical retinoids. It is important to keep in mind that in clinical trials of tretinoin and adapalene, rates of dropout due to adverse events typically were 1% to 2%; therefore, because many patients can tolerate generic tretinoin and adapalene, at current prices the lotion formulations of retinoids may not be cost-effective relative to these generics.¹⁴

Trifarotene cream 0.005%, a fourth-generation topical retinoid that is highly sensitive for retinoic acid receptor γ, recently was FDA approved for the treatment of acne. Although trifarotene is efficacious for both facial and truncal acne, there is a lack of active comparator data compared to other topical retinoids.¹⁸ In a 2023 network meta-analysis, trifarotene was found to be both less efficacious and less tolerable compared to other topical retinoids.¹⁹ Thus, it is unclear if trifarotene offers any improved efficacy compared to other options, and it comes at a much higher cost (Table). In a tolerability study, trifarotene was found to be significantly more irritating than tazarotene lotion 0.045% and adapalene gel 0.3% (P<.05).²⁰ Therefore, trifarotene cream 0.005% is unlikely to be a cost-effective option; in fact, it may be overall inferior to other topical retinoids, given its potentially lower tolerability.

Topical Antibiotics—There are 4 commonly prescribed topical antibiotics that are approved by the FDA for the treatment of acne: clindamycin, erythromycin, dapsone, and minocycline. The American Academy of Dermatology guidelines for the treatment of acne recommend concomitant use of BPO to prevent antibiotic resistance.⁵ Clindamycin is favored over erythromycin because of increasing antibiotic resistance to erythromycin.²¹ Inexpensive generic options in multiple vehicles (eg, solution, foam, gel) make clindamycin a highly cost-effective option when antibiotic therapy is desired as part of a topical regimen (Table).

The cost-effectiveness of dapsone gel and minocycline foam relative to clindamycin are less certain. Rates of resistance to minocycline are lower than clindamycin, and minocycline foam may be a reasonable alternative in patients who have not had success with other topical antibiotics, such as clindamycin.²² However, given the absence of comparative effectiveness data to suggest minocycline is more effective than clindamycin, it is difficult to justify the substantially higher cost for the typical patient. Although dapsone gel has been suggested as an option for adult women with acne, there are no data to support that it is any more effective than other topical antibiotics in this patient population.²³ As generic dapsone prices decrease, it may become a reasonable alternative to clindamycin. In addition, the antineutrophil properties of dapsone may be useful in other acneform and inflammatory eruptions, such as scalp folliculitis and folliculitis decalvans.²⁴

Combination Topicals—Current combination topical products include antibiotic and BPO, antibiotic and retinoid, and retinoid and BPO. Use of combination agents is recommended to reduce the risk for resistance and to enhance effectiveness. Combination products offer improved convenience, which is associated with better adherence and outcomes.²⁵ Generic fixed-dose adapalene-BPO can be a highly cost-effective option that can sometimes be less expensive than the individual component products (Table). Similarly, fixed-dose clindamycin-BPO also is likely to be highly cost-effective. A network meta-analysis found fixed-dose adapalene-BPO to be the most efficacious topical treatment, though it also was found to be the most irritating—more so than fixed-dose clindamycin-BPO, which may have similar efficacy.^14,26,27 Generic fixed-dose tretinoin-clindamycin offers improved convenience and adherence compared to the individual components, but it is more expensive, and its cost-effectiveness may be influenced by the importance of convenience for the patient.²⁵ An encapsulated, fixed-dose tretinoin 0.1%–BPO 3% cream is FDA approved for acne, but the cost is high and there is a lack of comparative effectiveness data demonstrating advantages over generic fixed-dose adapalene-BPO products.

Topical Antiandrogen—Clascoterone was introduced in 2020 as the first FDA-approved topical medication to target the hormonal pathogenesis of acne, inhibiting the androgen receptors in the sebaceous gland.²⁸ Because it is rapidly metabolized to cortexolone and does not have systemic antiandrogen effects, clascoterone can be used in both men and women with acne. In clinical trials, it had minimal side effects, including no evidence of irritability, which is an advantage over topical retinoids and BPO.²⁹ In addition, a phase 2 study found that clascoterone may have similar to superior efficacy to tretinoin cream 0.05%.³⁰ Although clascoterone has several strengths, including its efficacy, tolerability, and unique mechanism of action, its cost-effectiveness is limited due to its high cost (Table) and the need for twice-daily application, which reduces convenience. Clascoterone likely is best reserved for patients with a strong hormonal pathogenesis of their acne or difficulty tolerating other topicals, or as an additional therapy to complement other topicals.

Oral Antibiotics—Oral antibiotics are the most commonly prescribed systemic treatments for acne, particularly tetracyclines such as doxycycline, minocycline, and sarecycline.^31-34 Doxycycline and minocycline are considered first-line oral antibiotic therapy in the United States and are inexpensive and easily accessible.⁵ Doxycycline generally is recommended over minocycline given lack of evidence of superior efficacy of minocycline and concerns about severe adverse cutaneous reactions and drug-induced lupus with minocycline.³⁵

In recent years, there has been growing concern of the development of antibiotic resistance.⁵ Sarecycline is a narrow-spectrum tetracycline that was FDA approved for acne in 2018. In vitro studies demonstrate sarecycline maintains high efficacy against C acnes with less activity against other bacteria, particularly gram-negative enterobes.³⁶ The selectivity of sarecycline may lessen alterations of the gut microbiome seen with other oral antibiotics and reduce gastrointestinal tract side effects. Although comparative effectiveness studies are lacking, sarecycline was efficacious in phase 3 trials with few side effects compared with placebo.³⁷ However, at this time, given the absence of comparative effectiveness data and its high cost (Table), sarecycline likely is best reserved for patients with comorbidities (eg, gastrointestinal disease), those requiring long-term antibiotic therapy, or those with acne that has failed to respond to other oral antibiotics.

Hormonal Treatments—Hormonal treatments such as combined oral contraceptives (COCs) and spironolactone often are considered second-line options, though they may represent cost-effective and safe alternatives to oral antibiotics for women with moderate to severe acne.^38-41 There currently are 4 COCs approved by the FDA for the treatment of moderate acne in postmenarcheal females: drospirenone-ethinyl estradiol (Yaz [Bayer HealthCare Pharmaceuticals, Inc]), ethinyl estradiol-norgestimate (Ortho Tri-Cyclen [Ortho-McNeil Pharmaceuticals, Inc]), drospirenone-ethinyl estradiol-levomefolate (Beyaz [Bayer HealthCare Pharmaceuticals, Inc]), and ethinyl estradiol-norethindrone acetate-ferrous fumarate (Estrostep Fe [Allergan USA, Inc]).⁵ Treatment with COCs has been shown to cause substantial reductions in lesion counts across all lesion types compared to placebo, and a meta-analysis of 24 randomized trials conducted by Arowojolu et al⁴² demonstrated no consistent differences in acne reduction among different COCs.^43,44 Although oral antibiotics are associated with faster improvement than COCs, there is some evidence that they have similar efficacy at 6 months of therapy.⁴⁵ Combined oral contraceptives are inexpensive and likely reflect a highly cost-effective option (Table).

Spironolactone is an aldosterone inhibitor and androgen receptor blocker that is used off label to treat acne. It is one of the least expensive systemic medications for acne (Table). Although randomized controlled trials are lacking, several large case series support the effectiveness of spironolactone for women with acne.^38,46 In addition, observational data suggest spironolactone may have similar effectiveness to oral antibiotics.⁴¹ Spironolactone generally is well tolerated, with the most common adverse effects being menstrual irregularities, breast tenderness, and diuresis.^47,48 Many of these adverse effects are dose dependent and less likely with the dosing used in acne care. Additionally, menstrual irregularities can be reduced by concomitant use of a COC.⁴⁸

Although frequent potassium monitoring remains common among patients being treated with spironolactone, there is growing evidence to suggest that potassium monitoring is of low value in young healthy women with acne.^49-51 Reducing this laboratory monitoring likely represents an opportunity to provide higher-value care to patients being treated with spironolactone. However, laboratory monitoring should be considered if risk factors for hyperkalemia are present (eg, older age, comorbidities, medications).⁵¹

Isotretinoin—Isotretinoin is the most efficacious treatment available for acne and has the unique property of being able to induce a remission of acne activity for many patients.⁵ Although it remains modestly expensive (Table), it may be less costly overall relative to other treatments that may need continued use over many years because it can induce a remission of acne activity. As with spironolactone, frequent laboratory monitoring remains common among patients being treated with isotretinoin. There is no evidence to support checking complete blood cell counts.⁵² Several observational studies and a Delphi consensus support reduced monitoring, such as checking lipids and alanine aminotransferase at baseline and peak dose in otherwise young healthy patients.^53,54 A recent critically appraised topic published in the British Journal of Dermatology has proposed eliminating laboratory monitoring entirely.⁵⁵ Reducing laboratory monitoring for patients being treated with isotretinoin has been estimated to potentially save $100 million to $200 million per year in the United States.^52-54

Other Strategies to Reduce Patient Costs

Although choosing a cost-effective treatment approach is critical to preventing financial toxicity given poor coverage for acne care and the growth of high-deductible insurance plans, some patients may still experience high treatment costs.⁵⁶ Because pharmacy costs often are inflated, potentially related to practices of pharmacy benefit managers, it often is possible to find better prices than the presented list price, either by using platforms such as GoodRx or through direct-to-patient mail-order pharmacies such as Cost Plus Drug.⁵⁷ For branded medications, some patients may be eligible for patient-assistance programs, though they typically are not available for those with public insurance such as Medicare or Medicaid. Compounding pharmacies offer another approach to reduce cost and improve convenience for patients, but because the vehicle can influence the efficacy and tolerability of some topical medications, it is possible that these compounded formulations may not perform similarly to the original FDA-approved products.

Conclusion

For mild to moderate acne, multimodal topical therapy often is required. Fixed-dose combination adapalene-BPO and clindamycin-BPO are highly cost-effective options for most patients. Lotion formulations of topical retinoids may be useful in patients with difficulty tolerating other formulations. Clascoterone is a novel topical antiandrogen that is more expensive than other topical therapies but can complement other topical therapies and is well tolerated.

For moderate to severe acne, doxycycline or hormonal therapy (ie, COCs, spironolactone) are highly cost-effective options. Isotretinoin is recommended for severe or scarring acne. Reduced laboratory monitoring for spironolactone and isotretinoin is an opportunity to provide higher-value care.

In the United States, acne affects 85% of adolescents and can persist into adulthood at a prevalence of 30% to 50% in adult women. ^1,2 The pathogenesis of acne is multifactorial and involves hyperkeratinization of the follicle, bacterial colonization with Cutibacterium acnes , and increased androgen-induced sebum production, which together lead to inflammation. ^3,4 A wide range of treatment guideline–recommended options are available, including benzoyl peroxide (BPO), topical retinoids, topical and oral antibiotics, antiandrogens, and isotretinoin. ⁵ However, these options vary widely in their clinical uses, effectiveness, and costs.

Why Cost-effective Acne Care Matters

Out-of-pocket spending by patients on acne treatments can be substantial, with surveys finding that acne patients often spend hundreds to thousands of dollars per year.^6,7 In a poll conducted in 2019 by the Kaiser Family Foundation, 3 in 10 patients said they had not taken their medicine as prescribed because of costs.⁸ A mixed methods study by Ryskina et al⁹ found that 65% (17/26) of participants who reported primary nonadherence—intended to fill prescriptions but were unable to do so—cited cost or coverage-related barriers as the reason. With the continued rise of dermatologic drug prices and increased prevalence of high-deductible health plans, cost-effective treatment continues to grow in importance. Failure to consider cost-effective, patient-centered care may lead to increased financial toxicity, reduced adherence, and ultimately worse outcomes and patient satisfaction. We aim to review the cost-effectiveness of current prescription therapies for acne management and highlight the most cost-effective approaches to patients with mild to moderate acne as well as moderate to severe acne.

In this review, we will take a value-oriented framework.¹⁰ Value can be defined as the cost per outcome of interest. Therefore, a treatment does not necessarily need to be inexpensive to provide high value if it delivers outstanding clinical outcomes. In addition, we will focus on incremental cost-effectiveness relative to common alternatives (eg, a retinoid could deliver high value relative to a vehicle but still provide limited value compared to other available retinoids if it is more expensive but not more efficacious). When possible, we present data from cost-effectiveness studies.^11,12 We also use recent available price data obtained from GoodRx on August 11, 2023, to guide this discussion.¹³ However, as comparative-effectiveness and cost-effectiveness studies rarely are performed for acne medications, much of this discussion will be based on expert opinion.

Treatment Categories

Topical Retinoids—There currently are 4 topical retinoids that are approved by the US Food and Drug Administration (FDA) for the treatment of acne: tretinoin, tazarotene, trifarotene, and adapalene. These drugs are vitamin A derivatives that bind retinoic acid receptors and function as comedolytic and anti-inflammatory agents.⁵ In general, generic tretinoin and adapalene products have the lowest cost (Table).

In network meta-analyses, tretinoin and adapalene often are highly ranked topical treatment options with respect to efficacy.¹⁴ Combined with their low cost, generic tretinoin and adapalene likely are excellent initial options for topical therapy from the standpoint of cost-effectiveness.¹⁵ Adapalene may be preferred in many situations because of its better photostability and compatibility with BPO.

Due to the importance of the vehicle in determining retinoid tolerability, efforts have been made to use encapsulation and polymeric emulsion technology to improve tolerability. Recently, polymeric lotion formulations of tretinoin and tazarotene have become available. In a phase 2 study, tazarotene lotion 0.045% was found to have equivalent efficacy and superior tolerability to tazarotene cream 0.1%.¹⁶ Although head-to-head data are not available, it is likely that tretinoin lotion may offer similar tolerability improvements.¹⁷ Although these formulations currently are more costly, this improved tolerability may be critical for some patients to be able to use topical retinoids, and the additional cost may be worthwhile. In addition, as these products lose market exclusivity, they may become more affordable and similarly priced to other topical retinoids. It is important to keep in mind that in clinical trials of tretinoin and adapalene, rates of dropout due to adverse events typically were 1% to 2%; therefore, because many patients can tolerate generic tretinoin and adapalene, at current prices the lotion formulations of retinoids may not be cost-effective relative to these generics.¹⁴

Trifarotene cream 0.005%, a fourth-generation topical retinoid that is highly sensitive for retinoic acid receptor γ, recently was FDA approved for the treatment of acne. Although trifarotene is efficacious for both facial and truncal acne, there is a lack of active comparator data compared to other topical retinoids.¹⁸ In a 2023 network meta-analysis, trifarotene was found to be both less efficacious and less tolerable compared to other topical retinoids.¹⁹ Thus, it is unclear if trifarotene offers any improved efficacy compared to other options, and it comes at a much higher cost (Table). In a tolerability study, trifarotene was found to be significantly more irritating than tazarotene lotion 0.045% and adapalene gel 0.3% (P<.05).²⁰ Therefore, trifarotene cream 0.005% is unlikely to be a cost-effective option; in fact, it may be overall inferior to other topical retinoids, given its potentially lower tolerability.

Topical Antibiotics—There are 4 commonly prescribed topical antibiotics that are approved by the FDA for the treatment of acne: clindamycin, erythromycin, dapsone, and minocycline. The American Academy of Dermatology guidelines for the treatment of acne recommend concomitant use of BPO to prevent antibiotic resistance.⁵ Clindamycin is favored over erythromycin because of increasing antibiotic resistance to erythromycin.²¹ Inexpensive generic options in multiple vehicles (eg, solution, foam, gel) make clindamycin a highly cost-effective option when antibiotic therapy is desired as part of a topical regimen (Table).

The cost-effectiveness of dapsone gel and minocycline foam relative to clindamycin are less certain. Rates of resistance to minocycline are lower than clindamycin, and minocycline foam may be a reasonable alternative in patients who have not had success with other topical antibiotics, such as clindamycin.²² However, given the absence of comparative effectiveness data to suggest minocycline is more effective than clindamycin, it is difficult to justify the substantially higher cost for the typical patient. Although dapsone gel has been suggested as an option for adult women with acne, there are no data to support that it is any more effective than other topical antibiotics in this patient population.²³ As generic dapsone prices decrease, it may become a reasonable alternative to clindamycin. In addition, the antineutrophil properties of dapsone may be useful in other acneform and inflammatory eruptions, such as scalp folliculitis and folliculitis decalvans.²⁴

Combination Topicals—Current combination topical products include antibiotic and BPO, antibiotic and retinoid, and retinoid and BPO. Use of combination agents is recommended to reduce the risk for resistance and to enhance effectiveness. Combination products offer improved convenience, which is associated with better adherence and outcomes.²⁵ Generic fixed-dose adapalene-BPO can be a highly cost-effective option that can sometimes be less expensive than the individual component products (Table). Similarly, fixed-dose clindamycin-BPO also is likely to be highly cost-effective. A network meta-analysis found fixed-dose adapalene-BPO to be the most efficacious topical treatment, though it also was found to be the most irritating—more so than fixed-dose clindamycin-BPO, which may have similar efficacy.^14,26,27 Generic fixed-dose tretinoin-clindamycin offers improved convenience and adherence compared to the individual components, but it is more expensive, and its cost-effectiveness may be influenced by the importance of convenience for the patient.²⁵ An encapsulated, fixed-dose tretinoin 0.1%–BPO 3% cream is FDA approved for acne, but the cost is high and there is a lack of comparative effectiveness data demonstrating advantages over generic fixed-dose adapalene-BPO products.

Topical Antiandrogen—Clascoterone was introduced in 2020 as the first FDA-approved topical medication to target the hormonal pathogenesis of acne, inhibiting the androgen receptors in the sebaceous gland.²⁸ Because it is rapidly metabolized to cortexolone and does not have systemic antiandrogen effects, clascoterone can be used in both men and women with acne. In clinical trials, it had minimal side effects, including no evidence of irritability, which is an advantage over topical retinoids and BPO.²⁹ In addition, a phase 2 study found that clascoterone may have similar to superior efficacy to tretinoin cream 0.05%.³⁰ Although clascoterone has several strengths, including its efficacy, tolerability, and unique mechanism of action, its cost-effectiveness is limited due to its high cost (Table) and the need for twice-daily application, which reduces convenience. Clascoterone likely is best reserved for patients with a strong hormonal pathogenesis of their acne or difficulty tolerating other topicals, or as an additional therapy to complement other topicals.

Oral Antibiotics—Oral antibiotics are the most commonly prescribed systemic treatments for acne, particularly tetracyclines such as doxycycline, minocycline, and sarecycline.^31-34 Doxycycline and minocycline are considered first-line oral antibiotic therapy in the United States and are inexpensive and easily accessible.⁵ Doxycycline generally is recommended over minocycline given lack of evidence of superior efficacy of minocycline and concerns about severe adverse cutaneous reactions and drug-induced lupus with minocycline.³⁵

In recent years, there has been growing concern of the development of antibiotic resistance.⁵ Sarecycline is a narrow-spectrum tetracycline that was FDA approved for acne in 2018. In vitro studies demonstrate sarecycline maintains high efficacy against C acnes with less activity against other bacteria, particularly gram-negative enterobes.³⁶ The selectivity of sarecycline may lessen alterations of the gut microbiome seen with other oral antibiotics and reduce gastrointestinal tract side effects. Although comparative effectiveness studies are lacking, sarecycline was efficacious in phase 3 trials with few side effects compared with placebo.³⁷ However, at this time, given the absence of comparative effectiveness data and its high cost (Table), sarecycline likely is best reserved for patients with comorbidities (eg, gastrointestinal disease), those requiring long-term antibiotic therapy, or those with acne that has failed to respond to other oral antibiotics.

Hormonal Treatments—Hormonal treatments such as combined oral contraceptives (COCs) and spironolactone often are considered second-line options, though they may represent cost-effective and safe alternatives to oral antibiotics for women with moderate to severe acne.^38-41 There currently are 4 COCs approved by the FDA for the treatment of moderate acne in postmenarcheal females: drospirenone-ethinyl estradiol (Yaz [Bayer HealthCare Pharmaceuticals, Inc]), ethinyl estradiol-norgestimate (Ortho Tri-Cyclen [Ortho-McNeil Pharmaceuticals, Inc]), drospirenone-ethinyl estradiol-levomefolate (Beyaz [Bayer HealthCare Pharmaceuticals, Inc]), and ethinyl estradiol-norethindrone acetate-ferrous fumarate (Estrostep Fe [Allergan USA, Inc]).⁵ Treatment with COCs has been shown to cause substantial reductions in lesion counts across all lesion types compared to placebo, and a meta-analysis of 24 randomized trials conducted by Arowojolu et al⁴² demonstrated no consistent differences in acne reduction among different COCs.^43,44 Although oral antibiotics are associated with faster improvement than COCs, there is some evidence that they have similar efficacy at 6 months of therapy.⁴⁵ Combined oral contraceptives are inexpensive and likely reflect a highly cost-effective option (Table).

Spironolactone is an aldosterone inhibitor and androgen receptor blocker that is used off label to treat acne. It is one of the least expensive systemic medications for acne (Table). Although randomized controlled trials are lacking, several large case series support the effectiveness of spironolactone for women with acne.^38,46 In addition, observational data suggest spironolactone may have similar effectiveness to oral antibiotics.⁴¹ Spironolactone generally is well tolerated, with the most common adverse effects being menstrual irregularities, breast tenderness, and diuresis.^47,48 Many of these adverse effects are dose dependent and less likely with the dosing used in acne care. Additionally, menstrual irregularities can be reduced by concomitant use of a COC.⁴⁸

Although frequent potassium monitoring remains common among patients being treated with spironolactone, there is growing evidence to suggest that potassium monitoring is of low value in young healthy women with acne.^49-51 Reducing this laboratory monitoring likely represents an opportunity to provide higher-value care to patients being treated with spironolactone. However, laboratory monitoring should be considered if risk factors for hyperkalemia are present (eg, older age, comorbidities, medications).⁵¹

Isotretinoin—Isotretinoin is the most efficacious treatment available for acne and has the unique property of being able to induce a remission of acne activity for many patients.⁵ Although it remains modestly expensive (Table), it may be less costly overall relative to other treatments that may need continued use over many years because it can induce a remission of acne activity. As with spironolactone, frequent laboratory monitoring remains common among patients being treated with isotretinoin. There is no evidence to support checking complete blood cell counts.⁵² Several observational studies and a Delphi consensus support reduced monitoring, such as checking lipids and alanine aminotransferase at baseline and peak dose in otherwise young healthy patients.^53,54 A recent critically appraised topic published in the British Journal of Dermatology has proposed eliminating laboratory monitoring entirely.⁵⁵ Reducing laboratory monitoring for patients being treated with isotretinoin has been estimated to potentially save $100 million to $200 million per year in the United States.^52-54

Other Strategies to Reduce Patient Costs

Although choosing a cost-effective treatment approach is critical to preventing financial toxicity given poor coverage for acne care and the growth of high-deductible insurance plans, some patients may still experience high treatment costs.⁵⁶ Because pharmacy costs often are inflated, potentially related to practices of pharmacy benefit managers, it often is possible to find better prices than the presented list price, either by using platforms such as GoodRx or through direct-to-patient mail-order pharmacies such as Cost Plus Drug.⁵⁷ For branded medications, some patients may be eligible for patient-assistance programs, though they typically are not available for those with public insurance such as Medicare or Medicaid. Compounding pharmacies offer another approach to reduce cost and improve convenience for patients, but because the vehicle can influence the efficacy and tolerability of some topical medications, it is possible that these compounded formulations may not perform similarly to the original FDA-approved products.

Conclusion

For mild to moderate acne, multimodal topical therapy often is required. Fixed-dose combination adapalene-BPO and clindamycin-BPO are highly cost-effective options for most patients. Lotion formulations of topical retinoids may be useful in patients with difficulty tolerating other formulations. Clascoterone is a novel topical antiandrogen that is more expensive than other topical therapies but can complement other topical therapies and is well tolerated.

For moderate to severe acne, doxycycline or hormonal therapy (ie, COCs, spironolactone) are highly cost-effective options. Isotretinoin is recommended for severe or scarring acne. Reduced laboratory monitoring for spironolactone and isotretinoin is an opportunity to provide higher-value care.

The Diagnosis: Papular Acantholytic Dyskeratosis

The shave biopsy revealed suprabasal clefts associated with acantholytic and dyskeratotic cells as well as overlying hyperkeratosis. Direct immunofluorescence (DIF) was negative. Based on the combined clinical and histological findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD), a rare disease that clinically presents as small whitishgreyish papules with the potential to coalesce into larger plaques.^1,2 The condition predominantly manifests without symptoms, though pruritus and burning have been reported in affected sites. Most cases of PAD have been reported in older adults rather than in children or adolescents; it is more prevalent in women than in men. Lesions generally are localized to the penis, vulva, scrotum, inguinal folds, and perianal region.³ More specific terms have been used to describe this presentation such as papular acantholytic dyskeratosis of the anogenital region and papular acantholytic dyskeratosis of the genital-crural region. Histologic findings of PAD include epidermal acantholysis and dyskeratosis with hyperkeratosis and parakeratosis (quiz image).

The histologic differential diagnosis of PAD is broad due to its overlapping features with other diseases such as pemphigus vulgaris, Hailey-Hailey disease (HHD), Darier disease, and Grover disease. The acantholytic pathophysiology of these conditions involves dysfunction in cell adhesion markers. The correct diagnosis can be made by considering both the clinical location of involvement and histopathologic clues.

Pemphigus is a family of disorders involving mucocutaneous blistering of an autoimmune nature (Figure 1). Pemphigus vulgaris is the most prevalent variant of the pemphigus family, with symptomatically painful involvement of mucosal and cutaneous tissue. Autoantibodies to desmoglein 3 alone or both desmoglein 1 and 3 are present. Pemphigus vulgaris displays positive DIF findings with intercellular IgG and C3.

Hailey-Hailey disease (also known as benign familial pemphigus) is an autosomal-dominant disease that shares the acantholytic feature that is common in this class of diseases and caused by a defect in cell-cell adhesion as well as a loss of function in the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Blistering lesions typically appear in the neck, axillary, inguinal, or genital regions, and they can develop into crusted, exudate-filled lesions. No autoimmunity has been associated with this disease, unlike other diseases in the pemphigus family, and mutations in the ATP2C1 gene have been linked with dysregulation of cell-cell adhesion, particularly in cadherins and calcium-dependent cell adhesion processes. Histologically, HHD will show diffuse keratinocyte acantholysis with suprabasal clefting (Figure 2).⁴ Dyskeratosis is mild, if present at all, and dyskeratotic keratinocytes show a well-defined nucleus with cytoplasmic preservation. In contrast to HHD, PAD typically shows more dyskeratosis.

Darier disease (also known as keratosis follicularis) is an autosomal-dominant condition that normally presents with seborrheic eruptions in intertriginous areas, usually with onset during adolescence. Darier disease is caused by a loss-of-function mutation in the ATP2A2 gene found on chromosome 12q23-24.1 that encodes for the sarco(endo)plasmic reticulum calcium ATPase2 (SERCA2) enzymes involved in calcium-dependent transport of the endoplasmic reticulum within the cell. Due to calcium dysregulation, desmosomes are unable to carry out their function in cell-cell adhesion, resulting in keratinocyte acantholysis. Histopathology of Darier disease is identical to HHD but displays more dyskeratosis than HHD (Figure 3), possibly due to the endoplasmic reticulum calcium stores that are affected in Darier disease compared to the Golgi apparatus calcium stores that are implicated in HHD.5 The lowered endoplasmic reticulum calcium stores in Darier-White disease are associated with more pronounced dyskeratosis, which is seen histologically as corps ronds. Suprabasal hyperkeratosis also is found in Darier disease. The histopathologic findings of Darier disease and PAD can be identical, but the clinical presentations are distinct, with Darier disease typically manifesting as seborrheic eruptions appearing in adolescence and PAD presenting as small white papules in the anogenital or crural regions.

Grover disease (also referred to as transient acantholytic dermatosis) has an idiopathic pathophysiology. It clinically manifests with eruptions of erythematous, pruritic, truncal papules on the chest or back. Grover disease has a predilection for White men older than 50 years, and symptoms may be exacerbated in heat and diaphoretic conditions. Histologically, Grover disease may show acantholytic features seen in pemphigus vulgaris, HHD, and Darier disease; the pattern can only follow a specific disease or consist of a combination of all disease features (Figure 4). The acantholytic pattern of Grover disease was found to be similar to pemphigus vulgaris, Darier disease, pemphigus foliaceus, and HHD 47%, 18%, 9%, and 8% of the time, respectively. In 9% of cases, Grover disease will exhibit a mixed histopathology in which its acantholytic pattern will consist of a combination of features seen in the pemphigus family of diseases.6 Biopsy results showing mixed histologic patterns or a combination of different acantholytic features are suggestive of Grover disease over PAD. Moreover, the clinical distribution helps to differentiate Grover disease from PAD.

Because the histologic characteristics of these diseases overlap, certain nuances in clinical correlations and histology allow for distinction. In our patient, the diagnosis was most consistent with PAD based on the clinical manifestation of the disease and the biopsy results. Considering solely the clinical location of the lesions, Grover disease was a less likely diagnosis because our patient’s lesions were observed in the perianal region, not the truncal region as typically seen in Grover disease. Taking into account the DIF assay results in our patient, the pemphigus family of diseases also moved lower on the differential diagnosis. Finally, because the biopsy showed more dyskeratosis than would be present in HHD and also was inconsistent with the location and onset that would be expected to be seen in Darier disease, PAD was the most probable diagnosis. Interestingly, studies have shown mosaic mutations in ATP2A2 and ATP2C1 as possible causes of PAD, suggesting that this may be an allelic variant of Darier disease and HHD.7-9 No genetic testing was performed in our patient.

The Diagnosis: Papular Acantholytic Dyskeratosis

The shave biopsy revealed suprabasal clefts associated with acantholytic and dyskeratotic cells as well as overlying hyperkeratosis. Direct immunofluorescence (DIF) was negative. Based on the combined clinical and histological findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD), a rare disease that clinically presents as small whitishgreyish papules with the potential to coalesce into larger plaques.^1,2 The condition predominantly manifests without symptoms, though pruritus and burning have been reported in affected sites. Most cases of PAD have been reported in older adults rather than in children or adolescents; it is more prevalent in women than in men. Lesions generally are localized to the penis, vulva, scrotum, inguinal folds, and perianal region.³ More specific terms have been used to describe this presentation such as papular acantholytic dyskeratosis of the anogenital region and papular acantholytic dyskeratosis of the genital-crural region. Histologic findings of PAD include epidermal acantholysis and dyskeratosis with hyperkeratosis and parakeratosis (quiz image).

The histologic differential diagnosis of PAD is broad due to its overlapping features with other diseases such as pemphigus vulgaris, Hailey-Hailey disease (HHD), Darier disease, and Grover disease. The acantholytic pathophysiology of these conditions involves dysfunction in cell adhesion markers. The correct diagnosis can be made by considering both the clinical location of involvement and histopathologic clues.

Pemphigus is a family of disorders involving mucocutaneous blistering of an autoimmune nature (Figure 1). Pemphigus vulgaris is the most prevalent variant of the pemphigus family, with symptomatically painful involvement of mucosal and cutaneous tissue. Autoantibodies to desmoglein 3 alone or both desmoglein 1 and 3 are present. Pemphigus vulgaris displays positive DIF findings with intercellular IgG and C3.

Hailey-Hailey disease (also known as benign familial pemphigus) is an autosomal-dominant disease that shares the acantholytic feature that is common in this class of diseases and caused by a defect in cell-cell adhesion as well as a loss of function in the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Blistering lesions typically appear in the neck, axillary, inguinal, or genital regions, and they can develop into crusted, exudate-filled lesions. No autoimmunity has been associated with this disease, unlike other diseases in the pemphigus family, and mutations in the ATP2C1 gene have been linked with dysregulation of cell-cell adhesion, particularly in cadherins and calcium-dependent cell adhesion processes. Histologically, HHD will show diffuse keratinocyte acantholysis with suprabasal clefting (Figure 2).⁴ Dyskeratosis is mild, if present at all, and dyskeratotic keratinocytes show a well-defined nucleus with cytoplasmic preservation. In contrast to HHD, PAD typically shows more dyskeratosis.

Darier disease (also known as keratosis follicularis) is an autosomal-dominant condition that normally presents with seborrheic eruptions in intertriginous areas, usually with onset during adolescence. Darier disease is caused by a loss-of-function mutation in the ATP2A2 gene found on chromosome 12q23-24.1 that encodes for the sarco(endo)plasmic reticulum calcium ATPase2 (SERCA2) enzymes involved in calcium-dependent transport of the endoplasmic reticulum within the cell. Due to calcium dysregulation, desmosomes are unable to carry out their function in cell-cell adhesion, resulting in keratinocyte acantholysis. Histopathology of Darier disease is identical to HHD but displays more dyskeratosis than HHD (Figure 3), possibly due to the endoplasmic reticulum calcium stores that are affected in Darier disease compared to the Golgi apparatus calcium stores that are implicated in HHD.5 The lowered endoplasmic reticulum calcium stores in Darier-White disease are associated with more pronounced dyskeratosis, which is seen histologically as corps ronds. Suprabasal hyperkeratosis also is found in Darier disease. The histopathologic findings of Darier disease and PAD can be identical, but the clinical presentations are distinct, with Darier disease typically manifesting as seborrheic eruptions appearing in adolescence and PAD presenting as small white papules in the anogenital or crural regions.

Grover disease (also referred to as transient acantholytic dermatosis) has an idiopathic pathophysiology. It clinically manifests with eruptions of erythematous, pruritic, truncal papules on the chest or back. Grover disease has a predilection for White men older than 50 years, and symptoms may be exacerbated in heat and diaphoretic conditions. Histologically, Grover disease may show acantholytic features seen in pemphigus vulgaris, HHD, and Darier disease; the pattern can only follow a specific disease or consist of a combination of all disease features (Figure 4). The acantholytic pattern of Grover disease was found to be similar to pemphigus vulgaris, Darier disease, pemphigus foliaceus, and HHD 47%, 18%, 9%, and 8% of the time, respectively. In 9% of cases, Grover disease will exhibit a mixed histopathology in which its acantholytic pattern will consist of a combination of features seen in the pemphigus family of diseases.6 Biopsy results showing mixed histologic patterns or a combination of different acantholytic features are suggestive of Grover disease over PAD. Moreover, the clinical distribution helps to differentiate Grover disease from PAD.

Because the histologic characteristics of these diseases overlap, certain nuances in clinical correlations and histology allow for distinction. In our patient, the diagnosis was most consistent with PAD based on the clinical manifestation of the disease and the biopsy results. Considering solely the clinical location of the lesions, Grover disease was a less likely diagnosis because our patient’s lesions were observed in the perianal region, not the truncal region as typically seen in Grover disease. Taking into account the DIF assay results in our patient, the pemphigus family of diseases also moved lower on the differential diagnosis. Finally, because the biopsy showed more dyskeratosis than would be present in HHD and also was inconsistent with the location and onset that would be expected to be seen in Darier disease, PAD was the most probable diagnosis. Interestingly, studies have shown mosaic mutations in ATP2A2 and ATP2C1 as possible causes of PAD, suggesting that this may be an allelic variant of Darier disease and HHD.7-9 No genetic testing was performed in our patient.

The Diagnosis: Papular Acantholytic Dyskeratosis

The shave biopsy revealed suprabasal clefts associated with acantholytic and dyskeratotic cells as well as overlying hyperkeratosis. Direct immunofluorescence (DIF) was negative. Based on the combined clinical and histological findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD), a rare disease that clinically presents as small whitishgreyish papules with the potential to coalesce into larger plaques.^1,2 The condition predominantly manifests without symptoms, though pruritus and burning have been reported in affected sites. Most cases of PAD have been reported in older adults rather than in children or adolescents; it is more prevalent in women than in men. Lesions generally are localized to the penis, vulva, scrotum, inguinal folds, and perianal region.³ More specific terms have been used to describe this presentation such as papular acantholytic dyskeratosis of the anogenital region and papular acantholytic dyskeratosis of the genital-crural region. Histologic findings of PAD include epidermal acantholysis and dyskeratosis with hyperkeratosis and parakeratosis (quiz image).

The histologic differential diagnosis of PAD is broad due to its overlapping features with other diseases such as pemphigus vulgaris, Hailey-Hailey disease (HHD), Darier disease, and Grover disease. The acantholytic pathophysiology of these conditions involves dysfunction in cell adhesion markers. The correct diagnosis can be made by considering both the clinical location of involvement and histopathologic clues.

Pemphigus is a family of disorders involving mucocutaneous blistering of an autoimmune nature (Figure 1). Pemphigus vulgaris is the most prevalent variant of the pemphigus family, with symptomatically painful involvement of mucosal and cutaneous tissue. Autoantibodies to desmoglein 3 alone or both desmoglein 1 and 3 are present. Pemphigus vulgaris displays positive DIF findings with intercellular IgG and C3.

Hailey-Hailey disease (also known as benign familial pemphigus) is an autosomal-dominant disease that shares the acantholytic feature that is common in this class of diseases and caused by a defect in cell-cell adhesion as well as a loss of function in the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Blistering lesions typically appear in the neck, axillary, inguinal, or genital regions, and they can develop into crusted, exudate-filled lesions. No autoimmunity has been associated with this disease, unlike other diseases in the pemphigus family, and mutations in the ATP2C1 gene have been linked with dysregulation of cell-cell adhesion, particularly in cadherins and calcium-dependent cell adhesion processes. Histologically, HHD will show diffuse keratinocyte acantholysis with suprabasal clefting (Figure 2).⁴ Dyskeratosis is mild, if present at all, and dyskeratotic keratinocytes show a well-defined nucleus with cytoplasmic preservation. In contrast to HHD, PAD typically shows more dyskeratosis.

Darier disease (also known as keratosis follicularis) is an autosomal-dominant condition that normally presents with seborrheic eruptions in intertriginous areas, usually with onset during adolescence. Darier disease is caused by a loss-of-function mutation in the ATP2A2 gene found on chromosome 12q23-24.1 that encodes for the sarco(endo)plasmic reticulum calcium ATPase2 (SERCA2) enzymes involved in calcium-dependent transport of the endoplasmic reticulum within the cell. Due to calcium dysregulation, desmosomes are unable to carry out their function in cell-cell adhesion, resulting in keratinocyte acantholysis. Histopathology of Darier disease is identical to HHD but displays more dyskeratosis than HHD (Figure 3), possibly due to the endoplasmic reticulum calcium stores that are affected in Darier disease compared to the Golgi apparatus calcium stores that are implicated in HHD.5 The lowered endoplasmic reticulum calcium stores in Darier-White disease are associated with more pronounced dyskeratosis, which is seen histologically as corps ronds. Suprabasal hyperkeratosis also is found in Darier disease. The histopathologic findings of Darier disease and PAD can be identical, but the clinical presentations are distinct, with Darier disease typically manifesting as seborrheic eruptions appearing in adolescence and PAD presenting as small white papules in the anogenital or crural regions.

Grover disease (also referred to as transient acantholytic dermatosis) has an idiopathic pathophysiology. It clinically manifests with eruptions of erythematous, pruritic, truncal papules on the chest or back. Grover disease has a predilection for White men older than 50 years, and symptoms may be exacerbated in heat and diaphoretic conditions. Histologically, Grover disease may show acantholytic features seen in pemphigus vulgaris, HHD, and Darier disease; the pattern can only follow a specific disease or consist of a combination of all disease features (Figure 4). The acantholytic pattern of Grover disease was found to be similar to pemphigus vulgaris, Darier disease, pemphigus foliaceus, and HHD 47%, 18%, 9%, and 8% of the time, respectively. In 9% of cases, Grover disease will exhibit a mixed histopathology in which its acantholytic pattern will consist of a combination of features seen in the pemphigus family of diseases.6 Biopsy results showing mixed histologic patterns or a combination of different acantholytic features are suggestive of Grover disease over PAD. Moreover, the clinical distribution helps to differentiate Grover disease from PAD.

Because the histologic characteristics of these diseases overlap, certain nuances in clinical correlations and histology allow for distinction. In our patient, the diagnosis was most consistent with PAD based on the clinical manifestation of the disease and the biopsy results. Considering solely the clinical location of the lesions, Grover disease was a less likely diagnosis because our patient’s lesions were observed in the perianal region, not the truncal region as typically seen in Grover disease. Taking into account the DIF assay results in our patient, the pemphigus family of diseases also moved lower on the differential diagnosis. Finally, because the biopsy showed more dyskeratosis than would be present in HHD and also was inconsistent with the location and onset that would be expected to be seen in Darier disease, PAD was the most probable diagnosis. Interestingly, studies have shown mosaic mutations in ATP2A2 and ATP2C1 as possible causes of PAD, suggesting that this may be an allelic variant of Darier disease and HHD.7-9 No genetic testing was performed in our patient.