Cutis

Case Report

A 26-year-old woman with a medical history of newly diagnosed diabetes mellitus (DM), obesity, and asthma was evaluated as a hospital consultation with a vegetative plaque on the left lateral ankle of 13 months’ duration. The lesion first appeared as a red scaly rash that became purulent. The lesion had been treated with multiple rounds of topical antibiotics, oral antibiotics, topical antifungals, and corticosteroids without resolution. The patient denied pain or any decrease in ankle mobility. Review of systems was otherwise negative.

On physical examination, 3 large, pink, scaly, crusted plaques with surrounding erythema were observed (Figure 1A). On palpation, purulent drainage with a foul odor was noted in the area underlying the lesion. Initial punch biopsy demonstrated epidermal hyperplasia with neutrophil-rich sinus tracts consistent with pyoderma vegetans (PV)(Figure 2A). Tissue culture was positive for Staphylococcus aureus and Streptococcus anginosus. Cultures for both fungi and acid-fast bacilli were negative for growth.

The patient was treated with mupirocin ointment 2% and 3 months of cephalexin 250 mg twice daily, which cleared the purulent crust; however, serous drainage, ulceration, and erythema persisted. The patient needed an extended course of antibiotics, which had not been previously administered to clear the purulence. During this treatment regimen, the patient’s DM remained uncontrolled.

A second deeper punch biopsy revealed a layered granulomatous infiltrate with sclerosis throughout the dermis most consistent with necrobiosis lipoidica (NL)(Figure 2B). Direct immunofluorescence biopsy was negative. Once the PV was clear, betamethasone dipropionate ointment 0.05% was initiated to address the residual lesions (Figure 1B).

Physical examination combined with histopathologic findings and staphylococcal- and streptococcal-positive tissue cultures supported a diagnosis of NL with superimposed PV.

Comment

Necrobiosis lipoidica is a chronic granulomatous disease characterized by collagen degeneration, granulomatous formation, and endothelial wall thickening.¹ The condition is most commonly seen in association with insulin-dependent DM, though it also has been described in other inflammatory conditions. A case of NL in monozygotic twins has been reported, suggesting a genetic component in nondiabetic patients with NL.² Necrobiosis lipoidica affects females more often than males.

The pathogenesis of NL is not well understood but likely involves secondary microangiopathy because of glycoprotein deposition in vessel walls, leading to vascular thickening. Histopathology reveals palisading and necrobiotic granulomas comprising large confluent areas of necrobiosis throughout the dermis, giving a layered appearance.³

Clinically, NL presents with asymptomatic, well-circumscribed, violaceous papules and nodules that coalesce into plaques on the lower extremities, face, or trunk. The plaques have a central red-brown hue that progressively becomes more yellow and atrophic. The lesions can become eroded and ulcerated if left untreated.¹

Clinical diagnosis of NL can be challenging due to the similar clinical findings of other granulomatous lesions, such as granuloma annulare and cutaneous sarcoidosis. As reported by Pellicano and colleagues,⁴ dermoscopy has proved to be an excellent tool for differentiating these granulomatous skin lesions. Necrobiosis lipoidica demonstrates elongated serpentine telangiectases overlying a white structureless background, whereas granuloma annulare reveals orange-red structureless peripheral borders.⁵

Treatment of NL is difficult; patients often are refractory. Tight control of blood glucose alone has not been proven to cure NL. The mainstay of treatment is topical and intralesional corticosteroids at the active borders of the lesions. Tumor necrosis factor α inhibitors have shown some success, though recurrence has been reported.⁶ Other treatments, such as topical tretinoin and topical tacrolimus, may be of some benefit for atrophic NL lesions. Studies also have shown that skin grafting can be of surgical benefit in ulcerative NL with a low rate of recurrence.⁶ Control and management of DM plus lifestyle modifications may play a role in decreasing the severity of NL.⁷ Topical psoralen plus UVA light therapy and other experimental treatments, such as antiplatelet medications,⁸ also have been utilized.

The case of NL presented here was complicated by a superimposed suppurative infection consistent with PV, a rare chronic bacterial infection of the skin that presents with vegetative plaques. Pyoderma vegetans is most commonly observed in patients with underlying immunosuppression, likely secondary to DM in this case. Pyoderma vegetans is most often caused by S aureus and β-hemolytic streptococci. The clinical presentation of PV reveals verrucous vegetative plaques with pustules and abscesses. The borders of the lesions may be elevated and have a granulomatous appearance, thus complicating clinical diagnosis. There often is foul-smelling, purulent discharge within the plaques.⁹

Histopathology reveals pseudoepitheliomatous hyperplasia with abscesses and sinus tracts. An acute or chronic granulomatous inflammatory infiltrate may be observed. Basophilic fungus like granules are not seen within specimens of PV, which helps differentiate the disease from botryomycosis.¹⁰

There is no standardized treatment of PV; topical and systemic antibiotics are mainstays.¹⁰ One reported case of PV responded well to acitretin.⁹ Our patient responded well to 3 months of oral antibiotic therapy, followed by topical corticosteroids.

Case Report

A 26-year-old woman with a medical history of newly diagnosed diabetes mellitus (DM), obesity, and asthma was evaluated as a hospital consultation with a vegetative plaque on the left lateral ankle of 13 months’ duration. The lesion first appeared as a red scaly rash that became purulent. The lesion had been treated with multiple rounds of topical antibiotics, oral antibiotics, topical antifungals, and corticosteroids without resolution. The patient denied pain or any decrease in ankle mobility. Review of systems was otherwise negative.

On physical examination, 3 large, pink, scaly, crusted plaques with surrounding erythema were observed (Figure 1A). On palpation, purulent drainage with a foul odor was noted in the area underlying the lesion. Initial punch biopsy demonstrated epidermal hyperplasia with neutrophil-rich sinus tracts consistent with pyoderma vegetans (PV)(Figure 2A). Tissue culture was positive for Staphylococcus aureus and Streptococcus anginosus. Cultures for both fungi and acid-fast bacilli were negative for growth.

The patient was treated with mupirocin ointment 2% and 3 months of cephalexin 250 mg twice daily, which cleared the purulent crust; however, serous drainage, ulceration, and erythema persisted. The patient needed an extended course of antibiotics, which had not been previously administered to clear the purulence. During this treatment regimen, the patient’s DM remained uncontrolled.

A second deeper punch biopsy revealed a layered granulomatous infiltrate with sclerosis throughout the dermis most consistent with necrobiosis lipoidica (NL)(Figure 2B). Direct immunofluorescence biopsy was negative. Once the PV was clear, betamethasone dipropionate ointment 0.05% was initiated to address the residual lesions (Figure 1B).

Physical examination combined with histopathologic findings and staphylococcal- and streptococcal-positive tissue cultures supported a diagnosis of NL with superimposed PV.

Comment

Necrobiosis lipoidica is a chronic granulomatous disease characterized by collagen degeneration, granulomatous formation, and endothelial wall thickening.¹ The condition is most commonly seen in association with insulin-dependent DM, though it also has been described in other inflammatory conditions. A case of NL in monozygotic twins has been reported, suggesting a genetic component in nondiabetic patients with NL.² Necrobiosis lipoidica affects females more often than males.

The pathogenesis of NL is not well understood but likely involves secondary microangiopathy because of glycoprotein deposition in vessel walls, leading to vascular thickening. Histopathology reveals palisading and necrobiotic granulomas comprising large confluent areas of necrobiosis throughout the dermis, giving a layered appearance.³

Clinically, NL presents with asymptomatic, well-circumscribed, violaceous papules and nodules that coalesce into plaques on the lower extremities, face, or trunk. The plaques have a central red-brown hue that progressively becomes more yellow and atrophic. The lesions can become eroded and ulcerated if left untreated.¹

Clinical diagnosis of NL can be challenging due to the similar clinical findings of other granulomatous lesions, such as granuloma annulare and cutaneous sarcoidosis. As reported by Pellicano and colleagues,⁴ dermoscopy has proved to be an excellent tool for differentiating these granulomatous skin lesions. Necrobiosis lipoidica demonstrates elongated serpentine telangiectases overlying a white structureless background, whereas granuloma annulare reveals orange-red structureless peripheral borders.⁵

Treatment of NL is difficult; patients often are refractory. Tight control of blood glucose alone has not been proven to cure NL. The mainstay of treatment is topical and intralesional corticosteroids at the active borders of the lesions. Tumor necrosis factor α inhibitors have shown some success, though recurrence has been reported.⁶ Other treatments, such as topical tretinoin and topical tacrolimus, may be of some benefit for atrophic NL lesions. Studies also have shown that skin grafting can be of surgical benefit in ulcerative NL with a low rate of recurrence.⁶ Control and management of DM plus lifestyle modifications may play a role in decreasing the severity of NL.⁷ Topical psoralen plus UVA light therapy and other experimental treatments, such as antiplatelet medications,⁸ also have been utilized.

The case of NL presented here was complicated by a superimposed suppurative infection consistent with PV, a rare chronic bacterial infection of the skin that presents with vegetative plaques. Pyoderma vegetans is most commonly observed in patients with underlying immunosuppression, likely secondary to DM in this case. Pyoderma vegetans is most often caused by S aureus and β-hemolytic streptococci. The clinical presentation of PV reveals verrucous vegetative plaques with pustules and abscesses. The borders of the lesions may be elevated and have a granulomatous appearance, thus complicating clinical diagnosis. There often is foul-smelling, purulent discharge within the plaques.⁹

Histopathology reveals pseudoepitheliomatous hyperplasia with abscesses and sinus tracts. An acute or chronic granulomatous inflammatory infiltrate may be observed. Basophilic fungus like granules are not seen within specimens of PV, which helps differentiate the disease from botryomycosis.¹⁰

There is no standardized treatment of PV; topical and systemic antibiotics are mainstays.¹⁰ One reported case of PV responded well to acitretin.⁹ Our patient responded well to 3 months of oral antibiotic therapy, followed by topical corticosteroids.

Case Report

A 26-year-old woman with a medical history of newly diagnosed diabetes mellitus (DM), obesity, and asthma was evaluated as a hospital consultation with a vegetative plaque on the left lateral ankle of 13 months’ duration. The lesion first appeared as a red scaly rash that became purulent. The lesion had been treated with multiple rounds of topical antibiotics, oral antibiotics, topical antifungals, and corticosteroids without resolution. The patient denied pain or any decrease in ankle mobility. Review of systems was otherwise negative.

On physical examination, 3 large, pink, scaly, crusted plaques with surrounding erythema were observed (Figure 1A). On palpation, purulent drainage with a foul odor was noted in the area underlying the lesion. Initial punch biopsy demonstrated epidermal hyperplasia with neutrophil-rich sinus tracts consistent with pyoderma vegetans (PV)(Figure 2A). Tissue culture was positive for Staphylococcus aureus and Streptococcus anginosus. Cultures for both fungi and acid-fast bacilli were negative for growth.

The patient was treated with mupirocin ointment 2% and 3 months of cephalexin 250 mg twice daily, which cleared the purulent crust; however, serous drainage, ulceration, and erythema persisted. The patient needed an extended course of antibiotics, which had not been previously administered to clear the purulence. During this treatment regimen, the patient’s DM remained uncontrolled.

A second deeper punch biopsy revealed a layered granulomatous infiltrate with sclerosis throughout the dermis most consistent with necrobiosis lipoidica (NL)(Figure 2B). Direct immunofluorescence biopsy was negative. Once the PV was clear, betamethasone dipropionate ointment 0.05% was initiated to address the residual lesions (Figure 1B).

Physical examination combined with histopathologic findings and staphylococcal- and streptococcal-positive tissue cultures supported a diagnosis of NL with superimposed PV.

Comment

Necrobiosis lipoidica is a chronic granulomatous disease characterized by collagen degeneration, granulomatous formation, and endothelial wall thickening.¹ The condition is most commonly seen in association with insulin-dependent DM, though it also has been described in other inflammatory conditions. A case of NL in monozygotic twins has been reported, suggesting a genetic component in nondiabetic patients with NL.² Necrobiosis lipoidica affects females more often than males.

The pathogenesis of NL is not well understood but likely involves secondary microangiopathy because of glycoprotein deposition in vessel walls, leading to vascular thickening. Histopathology reveals palisading and necrobiotic granulomas comprising large confluent areas of necrobiosis throughout the dermis, giving a layered appearance.³

Clinically, NL presents with asymptomatic, well-circumscribed, violaceous papules and nodules that coalesce into plaques on the lower extremities, face, or trunk. The plaques have a central red-brown hue that progressively becomes more yellow and atrophic. The lesions can become eroded and ulcerated if left untreated.¹

Clinical diagnosis of NL can be challenging due to the similar clinical findings of other granulomatous lesions, such as granuloma annulare and cutaneous sarcoidosis. As reported by Pellicano and colleagues,⁴ dermoscopy has proved to be an excellent tool for differentiating these granulomatous skin lesions. Necrobiosis lipoidica demonstrates elongated serpentine telangiectases overlying a white structureless background, whereas granuloma annulare reveals orange-red structureless peripheral borders.⁵

Treatment of NL is difficult; patients often are refractory. Tight control of blood glucose alone has not been proven to cure NL. The mainstay of treatment is topical and intralesional corticosteroids at the active borders of the lesions. Tumor necrosis factor α inhibitors have shown some success, though recurrence has been reported.⁶ Other treatments, such as topical tretinoin and topical tacrolimus, may be of some benefit for atrophic NL lesions. Studies also have shown that skin grafting can be of surgical benefit in ulcerative NL with a low rate of recurrence.⁶ Control and management of DM plus lifestyle modifications may play a role in decreasing the severity of NL.⁷ Topical psoralen plus UVA light therapy and other experimental treatments, such as antiplatelet medications,⁸ also have been utilized.

The case of NL presented here was complicated by a superimposed suppurative infection consistent with PV, a rare chronic bacterial infection of the skin that presents with vegetative plaques. Pyoderma vegetans is most commonly observed in patients with underlying immunosuppression, likely secondary to DM in this case. Pyoderma vegetans is most often caused by S aureus and β-hemolytic streptococci. The clinical presentation of PV reveals verrucous vegetative plaques with pustules and abscesses. The borders of the lesions may be elevated and have a granulomatous appearance, thus complicating clinical diagnosis. There often is foul-smelling, purulent discharge within the plaques.⁹

Histopathology reveals pseudoepitheliomatous hyperplasia with abscesses and sinus tracts. An acute or chronic granulomatous inflammatory infiltrate may be observed. Basophilic fungus like granules are not seen within specimens of PV, which helps differentiate the disease from botryomycosis.¹⁰

There is no standardized treatment of PV; topical and systemic antibiotics are mainstays.¹⁰ One reported case of PV responded well to acitretin.⁹ Our patient responded well to 3 months of oral antibiotic therapy, followed by topical corticosteroids.

Idiopathic granulomatous mastitis (IGM) is rare during pregnancy; it typically is seen in women of childbearing potential from 6 months to 6 years postpartum.¹ Because of a temporal association with breastfeeding, it is believed that hyperprolactinemia² or an immune response to local lobular secretions might play a role in pathogenesis. Early misdiagnosis as bacterial mastitis is common, prompting multiple antibiotic regimens. When antibiotics fail, patients are worked up for inflammatory breast cancer, given the nonhealing breast nodules. Mammography, ultrasonography, and fine-needle aspiration often are unable to rule out carcinoma, warranting excisional biopsies of nodules. The patient is then referred to rheumatology for potential sarcoidosis or to dermatology for IGM. In either case, the workup should be similar, but additional history focused on behavior and medications is essential in suspected IGM, given the association with hyperprolactinemia.

Because IGM is rare, there are no randomized, placebo-controlled trials of treatment efficacy. In many cases, patients undergo complete mastectomy, which is curative but may be psychologically and physically impactful in young women. In some cases, high-dose corticosteroids have been successful; however, because the IGM process can last longer than 2 years, patients treated in this manner are exposed to steroid morbidities.¹

We report 3 cases of IGM that add to the literature on possible contributing factors, clinical presentations, and treatments for this disease. We also demonstrate that appropriate trigger identification and steroid-sparing agents, specifically methotrexate, can be breast-saving as they can alleviate this debilitating condition, obviating the need for radical surgical intervention.

CASE REPORTS 

Patient 1

A 40-year-old woman with a 4-year history of breastfeeding noted a grape-sized nodule on the left breast that grew to the size of a grapefruit after 2 weeks. Ulceration and drainage periodically occurred, forming pink plaques along the lateral aspects of the breast after healing. Her primary care provider suspected infectious mastitis; she was given an oral antibiotic (cephalexin) and intravenous antibiotics without improvement.

Imaging
Subsequent magnetic resonance imaging revealed a large, irregular, enhancing mass within the outer left breast (6.5 cm at greatest dimension) with additional surrounding amorphous enhancement highly suspicious for malignancy. There also were multiple prominent left axillary lymph nodes, with the largest demonstrating a cortical thickness of 8 mm.

Biopsy
Core breast biopsy showed benign tissue with fat necrosis. Fine-needle aspiration revealed few benign ductal cells and rare histiocytes; because these findings were nondiagnostic and cancer was still a consideration, the patient underwent excisional biopsy.

Histologic sections of breast tissue showed extensive lobulocentric inflammation comprising histiocytes and lymphocytes, with neutrophils admixed and forming microabscesses (Figure 1A). Multinucleated giant cells and single-cell necrosis were seen, but true caseous necrosis was absent (Figure 1B). Duct spaces often contained inflammatory cells or secretions. Special stains for fungal and acid-fast bacterial microorganisms were negative.

Granulomatous lobular mastitis was diagnosed, and the patient was referred to dermatology. On presentation to dermatology, the left breast showed a 6-cm area of firm induration and overlying peau d’orange change to the epidermis (Figure 2A). Based on pathologic analysis, she was worked up for a possible granulomatous etiology. Negative purified protein derivative (tuberculin)(PPD) and a normal chest radiograph ruled out tuberculosis. Normal chest radiography, serum Ca²⁺ and angiotensin-converting enzyme (ACE) levels, and ophthalmology examination ruled out sarcoidosis.

The patient reported she continued breastfeeding her 4-year-old son. Additionally, she had been started on trazadone and buspirone for alcohol abuse recovery, then switched to and maintained on fluoxetine 1 year before developing these symptoms.

Buspirone, fluoxetine, and prolonged breastfeeding all contribute to hyperprolactinemia, a possible trigger of IGM. The patient was therefore advised to stop breastfeeding and to be switched from fluoxetine to a medication that would not increase the prolactin level. She did not require methotrexate treatment because her condition resolved rapidly after breastfeeding and fluoxetine were discontinued (Figure 2B).

Patient 2 

A 40-year-old woman with no history of breastfeeding who gave birth 4.5 years prior presented to her primary care provider with a painful breast lump and rash on the right breast of 2 months’ duration. Infectious mastitis was suspected; she was given cephalexin and clindamycin without improvement of symptoms.

Imaging
Mammography and ultrasonography were nondiagnostic.

Biopsy
Breast biopsy showed tissue with large expanses of histiocytes, neutrophils, lymphocytes, plasma cells, and multinucleated giant cells (Figure 3A). Many discrete granulomas were seen against this mixed inflammatory background, associated with focal fat necrosis (Figure 3B). Special stains were negative for microorganisms. Histologic findings were consistent with granulomatous mastitis.

On presentation to dermatology, the patient was worked up for a possible granulomatous etiology, which included a negative PPD, as well as a normal chest radiograph, serum Ca²⁺ and ACE levels, and ophthalmology examination. Review of symptoms (ROS),medical history, and medication review were unremarkable.

By exclusion, the patient was given a diagnosis of IGM and started on methotrexate (15 mg weekly) with folic acid (1 mg daily). The condition of the right breast improved within 4 weeks of starting methotrexate; however, methotrexate was increased to 30 mg weekly because of occasional flares. The patient remained on methotrexate without further IGM flares for 8 months compared to prior unremitting pain and drainage. She was then tapered from methotrexate over 6 weeks without additional flares.

A 27-year-old woman who gave birth 2 years prior and discontinued breastfeeding 6 weeks after delivery noted bilateral breast rashes for several months. The lesions were growing in size, tender, and draining. Her primary care provider suspected infectious mastitis and prescribed antibiotics, which were ineffective.

Biopsy
Breast core biopsy showed histologic findings similar to patients 1 and 2, including lobulocentric mixed inflammation, neutrophilic microabscesses, and scattered discrete granulomas. Microorganisms were not found using special stains. Breast cancer was ruled out, and granulomatous mastitis was diagnosed.

Referral to Dermatology
Two years earlier, the patient tested positive for latent tuberculosis and was prescribed a 9-month regimen of isoniazid. At the current presentation, she did not have symptoms of active tuberculosis on ROS (ie, no cough, hemoptysis, weight loss, night sweats); a chest radiograph was normal. Additionally, serum Ca²⁺ and ACE levels as well as an ophthalmology examination were normal, and she was not taking any medications known to increase the prolactin level.

The patient was started on methotrexate (12.5 mg weekly) and folic acid (1 mg daily). She had 1 IGM flare and was given a tapering regimen of prednisone. She received methotrexate for 14 months, tapered during the final 3 months. She has been off methotrexate for 3 years without IGM flares and appears to be in complete remission.

COMMENT

We report 3 cases of IGM, which contribute to the literature on possible presentations, causes, and conservative treatment of this rare connective-tissue disorder.

Differential Diagnosis

The time between recognition of symptoms and diagnosis and treatment of IGM often is prolonged because IGM can present similarly to other disorders, such as infection, breast cancer, tuberculosis, and sarcoidosis. Idiopathic granulomatous mastitis is a diagnosis of exclusion, made after obtaining evidence of granulomatous inflammation on breast biopsy and ruling out other granulomatous disorders, such as tuberculosis and sarcoidosis (Table 1).^3,4

Tuberculosis
A full ROS and a PPD test or T-SPOT.TB test can be helpful in ruling out tuberculosis; because anergy occurs in some patients, tuberculosis should be evaluated in the context of known immunosuppression or human immunodeficiency virus status, or in the case of miliary tuberculosis.

Chest radiography findings classically showing upper lobe infiltrates with cavities in active tuberculosis also should be sought.³ Ziehl-Neelsen staining of 2 sputum specimens, assessed by conventional light microscopy at the time of tissue biopsy has 64% sensitivity and 98% specificity for detecting Mycobacterium tuberculosis; auramine O staining, examined with light-emitting diode fluorescence microscopy, has 73% sensitivity and 93% specificity.⁵

Sarcoidosis
Because more than 90% of sarcoid patients have lung disease, a chest radiograph is used to screen for hilar lymphadenopathy.³ An elevated serum ACE level also can be helpful in diagnosis, but patients do not always have increased ACE, which can occur in other diseases, such as hyperthyroidism and miliary tuberculosis. Sarcoid granulomas can increase active vitamin D production, which in turn increases serum Ca²⁺ in 10% of sarcoid patients. Last, an ophthalmology evaluation should be obtained to rule out anterior or posterior uveitis that can occur in sarcoidosis and initially remain asymptomatic.³ Once these other causes of granulomatous inflammation have been ruled out, a diagnosis of IGM can be made.

Prolactinoma
Prolactinoma is an important cause of hyperprolactinemia that can be screened for based on ROS and the serum prolactin level. Prolactinoma can cause oligomenorrhea or amenorrhea and galactorrhea in 90% and 80% of premenopausal women, respectively, as well as erectile dysfunction and decreased libido in men. Infertility, headache, and visual impairment may be experienced in both sexes.⁴

A normal prolactin level is less than 25 μg/L; more than 25 μg/L but less than 100 μg/L usually is due to certain drugs (eTable),^6-11 estrogen, or idiopathic reasons; and more than 150 μg/L usually is due to prolactinoma.⁵ In many cases, removal of hyperprolactinemia-precipitating factors can resolve disease, as in patient 1. If symptoms continue or precipitating factors are absent, IGM symptom-based treatment should be administered.

Course and Management

Idiopathic granulomatous mastitis is self-limited and usually resolves within 2 years. Therefore, the goal of treatment is to suppress associated pain and drainage until the active inflammatory phase of IGM self-resolves. An established protocol for treating IGM does not exist, but common treatments include corticosteroids, methotrexate, and limited or wide surgical excision (Table 2).^12-16 Before beginning any of these treatments, IGM triggers, such as breastfeeding and drugs that induce hyperprolactinemia, should be removed.

It is important to consider which treatment option is best for limiting disease recurrence and adverse effects (AEs). Keep in mind that the available data are limited, as there are no randomized controlled trials looking at these treatments. Nevertheless, we recommend methotrexate as first line because it resolves granulomatous inflammation symptoms without invasive surgery, while limiting corticosteroid AEs.¹²

With or without concurrent use of corticosteroids, surgical excision typically is the mainstay of treatment. However, surgical excision of IGM lesions can be complicated by abscess formation, fistula, and chronic pyogenic secretions, in addition to a 5% to 50% rate of recurrence of disease.^12-14 Limited excision often is insufficient; therefore, wide local excision, in which negative margins around granulomatous inflammation are obtained, is the surgical modality of choice.¹⁴ Wide local excision can be disfiguring to the breast in young women affected by IGM, making it an undesirable treatment option.

Corticosteroids often have been used to treat IGM, but their efficacy is variable, symptoms can recur upon drug removal, and remarkable AEs can result from long-term use.¹² Additionally, corticosteroid therapy often is used in combination with excision, making it difficult to determine the extent to which corticosteroids or excision are more beneficial. In a prospective observational study, corticosteroid therapy alone resolved 80% of IGM symptoms after 159 days on average. After complete symptom resolution, 23% of patients had disease recurrence.⁹ Observed AEs included gastritis, weight gain, osteoporosis, glucose intolerance, and Cushing syndrome.^12,15

Methotrexate for IGM has not been reviewed in a randomized controlled trial; case reports have shown 83% symptom resolution, with 17% recurrence and limited long-term AEs.¹² Because the active phase of IGM can persist for 2 years, immunosuppressive therapy with limited AEs is necessary. Many AEs can occur when high-dose methotrexate is given for cancer treatment. Low-dose methotrexate has been extensively studied in long-term treatment of rheumatoid arthritis. Adverse effects may include gastrointestinal tract upset and hepatic dysfunction, which are limited when given with folic acid.

Regardless of folic acid cotreatment, stomatitis may occur. Women should use an effective method of birth control because severe birth defects may occur on even low-dose methotrexate.¹⁶

Compared to corticosteroid or surgical treatment, we recommend low-dose methotrexate therapy based on its high efficacy with limited AEs. An occasional mild flare of IGM symptoms with methotrexate is not unusual. If it occurs, corticosteroids can be added and tapered for as long as 2 weeks to speed up resolution of flares while reducing long-term AEs of corticosteroids.

Surgical excision can be performed in cases refractory to all systemic therapies.

CONCLUSION

Idiopathic granulomatous mastitis is a rare granulomatous breast disorder that can have a prolonged time to diagnosis, delaying proper treatment. Many cases self-resolve, but more severe cases can persist for a long period before adequate symptomatic treatment is achieved by methotrexate, corticosteroids, or surgical excision. Before using these therapies, it is important to identify and remove contributing factors, such as long-term breastfeeding and drugs that induce hyperprolactinemia. Improving the rate of IGM diagnosis and treatment would greatly benefit these patients. We report 1 case in which removal of possible precipitating IGM factors led to symptom resolution and 2 cases in which methotrexate was an effective IGM treatment that limited the need for invasive procedures and corticosteroid AEs.

Idiopathic granulomatous mastitis (IGM) is rare during pregnancy; it typically is seen in women of childbearing potential from 6 months to 6 years postpartum.¹ Because of a temporal association with breastfeeding, it is believed that hyperprolactinemia² or an immune response to local lobular secretions might play a role in pathogenesis. Early misdiagnosis as bacterial mastitis is common, prompting multiple antibiotic regimens. When antibiotics fail, patients are worked up for inflammatory breast cancer, given the nonhealing breast nodules. Mammography, ultrasonography, and fine-needle aspiration often are unable to rule out carcinoma, warranting excisional biopsies of nodules. The patient is then referred to rheumatology for potential sarcoidosis or to dermatology for IGM. In either case, the workup should be similar, but additional history focused on behavior and medications is essential in suspected IGM, given the association with hyperprolactinemia.

Because IGM is rare, there are no randomized, placebo-controlled trials of treatment efficacy. In many cases, patients undergo complete mastectomy, which is curative but may be psychologically and physically impactful in young women. In some cases, high-dose corticosteroids have been successful; however, because the IGM process can last longer than 2 years, patients treated in this manner are exposed to steroid morbidities.¹

We report 3 cases of IGM that add to the literature on possible contributing factors, clinical presentations, and treatments for this disease. We also demonstrate that appropriate trigger identification and steroid-sparing agents, specifically methotrexate, can be breast-saving as they can alleviate this debilitating condition, obviating the need for radical surgical intervention.

CASE REPORTS 

Patient 1

A 40-year-old woman with a 4-year history of breastfeeding noted a grape-sized nodule on the left breast that grew to the size of a grapefruit after 2 weeks. Ulceration and drainage periodically occurred, forming pink plaques along the lateral aspects of the breast after healing. Her primary care provider suspected infectious mastitis; she was given an oral antibiotic (cephalexin) and intravenous antibiotics without improvement.

Imaging
Subsequent magnetic resonance imaging revealed a large, irregular, enhancing mass within the outer left breast (6.5 cm at greatest dimension) with additional surrounding amorphous enhancement highly suspicious for malignancy. There also were multiple prominent left axillary lymph nodes, with the largest demonstrating a cortical thickness of 8 mm.

Biopsy
Core breast biopsy showed benign tissue with fat necrosis. Fine-needle aspiration revealed few benign ductal cells and rare histiocytes; because these findings were nondiagnostic and cancer was still a consideration, the patient underwent excisional biopsy.

Histologic sections of breast tissue showed extensive lobulocentric inflammation comprising histiocytes and lymphocytes, with neutrophils admixed and forming microabscesses (Figure 1A). Multinucleated giant cells and single-cell necrosis were seen, but true caseous necrosis was absent (Figure 1B). Duct spaces often contained inflammatory cells or secretions. Special stains for fungal and acid-fast bacterial microorganisms were negative.

Granulomatous lobular mastitis was diagnosed, and the patient was referred to dermatology. On presentation to dermatology, the left breast showed a 6-cm area of firm induration and overlying peau d’orange change to the epidermis (Figure 2A). Based on pathologic analysis, she was worked up for a possible granulomatous etiology. Negative purified protein derivative (tuberculin)(PPD) and a normal chest radiograph ruled out tuberculosis. Normal chest radiography, serum Ca²⁺ and angiotensin-converting enzyme (ACE) levels, and ophthalmology examination ruled out sarcoidosis.

The patient reported she continued breastfeeding her 4-year-old son. Additionally, she had been started on trazadone and buspirone for alcohol abuse recovery, then switched to and maintained on fluoxetine 1 year before developing these symptoms.

Buspirone, fluoxetine, and prolonged breastfeeding all contribute to hyperprolactinemia, a possible trigger of IGM. The patient was therefore advised to stop breastfeeding and to be switched from fluoxetine to a medication that would not increase the prolactin level. She did not require methotrexate treatment because her condition resolved rapidly after breastfeeding and fluoxetine were discontinued (Figure 2B).

Patient 2 

A 40-year-old woman with no history of breastfeeding who gave birth 4.5 years prior presented to her primary care provider with a painful breast lump and rash on the right breast of 2 months’ duration. Infectious mastitis was suspected; she was given cephalexin and clindamycin without improvement of symptoms.

Imaging
Mammography and ultrasonography were nondiagnostic.

Biopsy
Breast biopsy showed tissue with large expanses of histiocytes, neutrophils, lymphocytes, plasma cells, and multinucleated giant cells (Figure 3A). Many discrete granulomas were seen against this mixed inflammatory background, associated with focal fat necrosis (Figure 3B). Special stains were negative for microorganisms. Histologic findings were consistent with granulomatous mastitis.

On presentation to dermatology, the patient was worked up for a possible granulomatous etiology, which included a negative PPD, as well as a normal chest radiograph, serum Ca²⁺ and ACE levels, and ophthalmology examination. Review of symptoms (ROS),medical history, and medication review were unremarkable.

By exclusion, the patient was given a diagnosis of IGM and started on methotrexate (15 mg weekly) with folic acid (1 mg daily). The condition of the right breast improved within 4 weeks of starting methotrexate; however, methotrexate was increased to 30 mg weekly because of occasional flares. The patient remained on methotrexate without further IGM flares for 8 months compared to prior unremitting pain and drainage. She was then tapered from methotrexate over 6 weeks without additional flares.

A 27-year-old woman who gave birth 2 years prior and discontinued breastfeeding 6 weeks after delivery noted bilateral breast rashes for several months. The lesions were growing in size, tender, and draining. Her primary care provider suspected infectious mastitis and prescribed antibiotics, which were ineffective.

Biopsy
Breast core biopsy showed histologic findings similar to patients 1 and 2, including lobulocentric mixed inflammation, neutrophilic microabscesses, and scattered discrete granulomas. Microorganisms were not found using special stains. Breast cancer was ruled out, and granulomatous mastitis was diagnosed.

Referral to Dermatology
Two years earlier, the patient tested positive for latent tuberculosis and was prescribed a 9-month regimen of isoniazid. At the current presentation, she did not have symptoms of active tuberculosis on ROS (ie, no cough, hemoptysis, weight loss, night sweats); a chest radiograph was normal. Additionally, serum Ca²⁺ and ACE levels as well as an ophthalmology examination were normal, and she was not taking any medications known to increase the prolactin level.

The patient was started on methotrexate (12.5 mg weekly) and folic acid (1 mg daily). She had 1 IGM flare and was given a tapering regimen of prednisone. She received methotrexate for 14 months, tapered during the final 3 months. She has been off methotrexate for 3 years without IGM flares and appears to be in complete remission.

COMMENT

We report 3 cases of IGM, which contribute to the literature on possible presentations, causes, and conservative treatment of this rare connective-tissue disorder.

Differential Diagnosis

The time between recognition of symptoms and diagnosis and treatment of IGM often is prolonged because IGM can present similarly to other disorders, such as infection, breast cancer, tuberculosis, and sarcoidosis. Idiopathic granulomatous mastitis is a diagnosis of exclusion, made after obtaining evidence of granulomatous inflammation on breast biopsy and ruling out other granulomatous disorders, such as tuberculosis and sarcoidosis (Table 1).^3,4

Tuberculosis
A full ROS and a PPD test or T-SPOT.TB test can be helpful in ruling out tuberculosis; because anergy occurs in some patients, tuberculosis should be evaluated in the context of known immunosuppression or human immunodeficiency virus status, or in the case of miliary tuberculosis.

Chest radiography findings classically showing upper lobe infiltrates with cavities in active tuberculosis also should be sought.³ Ziehl-Neelsen staining of 2 sputum specimens, assessed by conventional light microscopy at the time of tissue biopsy has 64% sensitivity and 98% specificity for detecting Mycobacterium tuberculosis; auramine O staining, examined with light-emitting diode fluorescence microscopy, has 73% sensitivity and 93% specificity.⁵

Sarcoidosis
Because more than 90% of sarcoid patients have lung disease, a chest radiograph is used to screen for hilar lymphadenopathy.³ An elevated serum ACE level also can be helpful in diagnosis, but patients do not always have increased ACE, which can occur in other diseases, such as hyperthyroidism and miliary tuberculosis. Sarcoid granulomas can increase active vitamin D production, which in turn increases serum Ca²⁺ in 10% of sarcoid patients. Last, an ophthalmology evaluation should be obtained to rule out anterior or posterior uveitis that can occur in sarcoidosis and initially remain asymptomatic.³ Once these other causes of granulomatous inflammation have been ruled out, a diagnosis of IGM can be made.

Prolactinoma
Prolactinoma is an important cause of hyperprolactinemia that can be screened for based on ROS and the serum prolactin level. Prolactinoma can cause oligomenorrhea or amenorrhea and galactorrhea in 90% and 80% of premenopausal women, respectively, as well as erectile dysfunction and decreased libido in men. Infertility, headache, and visual impairment may be experienced in both sexes.⁴

A normal prolactin level is less than 25 μg/L; more than 25 μg/L but less than 100 μg/L usually is due to certain drugs (eTable),^6-11 estrogen, or idiopathic reasons; and more than 150 μg/L usually is due to prolactinoma.⁵ In many cases, removal of hyperprolactinemia-precipitating factors can resolve disease, as in patient 1. If symptoms continue or precipitating factors are absent, IGM symptom-based treatment should be administered.

Course and Management

Idiopathic granulomatous mastitis is self-limited and usually resolves within 2 years. Therefore, the goal of treatment is to suppress associated pain and drainage until the active inflammatory phase of IGM self-resolves. An established protocol for treating IGM does not exist, but common treatments include corticosteroids, methotrexate, and limited or wide surgical excision (Table 2).^12-16 Before beginning any of these treatments, IGM triggers, such as breastfeeding and drugs that induce hyperprolactinemia, should be removed.

It is important to consider which treatment option is best for limiting disease recurrence and adverse effects (AEs). Keep in mind that the available data are limited, as there are no randomized controlled trials looking at these treatments. Nevertheless, we recommend methotrexate as first line because it resolves granulomatous inflammation symptoms without invasive surgery, while limiting corticosteroid AEs.¹²

With or without concurrent use of corticosteroids, surgical excision typically is the mainstay of treatment. However, surgical excision of IGM lesions can be complicated by abscess formation, fistula, and chronic pyogenic secretions, in addition to a 5% to 50% rate of recurrence of disease.^12-14 Limited excision often is insufficient; therefore, wide local excision, in which negative margins around granulomatous inflammation are obtained, is the surgical modality of choice.¹⁴ Wide local excision can be disfiguring to the breast in young women affected by IGM, making it an undesirable treatment option.

Corticosteroids often have been used to treat IGM, but their efficacy is variable, symptoms can recur upon drug removal, and remarkable AEs can result from long-term use.¹² Additionally, corticosteroid therapy often is used in combination with excision, making it difficult to determine the extent to which corticosteroids or excision are more beneficial. In a prospective observational study, corticosteroid therapy alone resolved 80% of IGM symptoms after 159 days on average. After complete symptom resolution, 23% of patients had disease recurrence.⁹ Observed AEs included gastritis, weight gain, osteoporosis, glucose intolerance, and Cushing syndrome.^12,15

Methotrexate for IGM has not been reviewed in a randomized controlled trial; case reports have shown 83% symptom resolution, with 17% recurrence and limited long-term AEs.¹² Because the active phase of IGM can persist for 2 years, immunosuppressive therapy with limited AEs is necessary. Many AEs can occur when high-dose methotrexate is given for cancer treatment. Low-dose methotrexate has been extensively studied in long-term treatment of rheumatoid arthritis. Adverse effects may include gastrointestinal tract upset and hepatic dysfunction, which are limited when given with folic acid.

Regardless of folic acid cotreatment, stomatitis may occur. Women should use an effective method of birth control because severe birth defects may occur on even low-dose methotrexate.¹⁶

Compared to corticosteroid or surgical treatment, we recommend low-dose methotrexate therapy based on its high efficacy with limited AEs. An occasional mild flare of IGM symptoms with methotrexate is not unusual. If it occurs, corticosteroids can be added and tapered for as long as 2 weeks to speed up resolution of flares while reducing long-term AEs of corticosteroids.

Surgical excision can be performed in cases refractory to all systemic therapies.

CONCLUSION

Idiopathic granulomatous mastitis is a rare granulomatous breast disorder that can have a prolonged time to diagnosis, delaying proper treatment. Many cases self-resolve, but more severe cases can persist for a long period before adequate symptomatic treatment is achieved by methotrexate, corticosteroids, or surgical excision. Before using these therapies, it is important to identify and remove contributing factors, such as long-term breastfeeding and drugs that induce hyperprolactinemia. Improving the rate of IGM diagnosis and treatment would greatly benefit these patients. We report 1 case in which removal of possible precipitating IGM factors led to symptom resolution and 2 cases in which methotrexate was an effective IGM treatment that limited the need for invasive procedures and corticosteroid AEs.

Idiopathic granulomatous mastitis (IGM) is rare during pregnancy; it typically is seen in women of childbearing potential from 6 months to 6 years postpartum.¹ Because of a temporal association with breastfeeding, it is believed that hyperprolactinemia² or an immune response to local lobular secretions might play a role in pathogenesis. Early misdiagnosis as bacterial mastitis is common, prompting multiple antibiotic regimens. When antibiotics fail, patients are worked up for inflammatory breast cancer, given the nonhealing breast nodules. Mammography, ultrasonography, and fine-needle aspiration often are unable to rule out carcinoma, warranting excisional biopsies of nodules. The patient is then referred to rheumatology for potential sarcoidosis or to dermatology for IGM. In either case, the workup should be similar, but additional history focused on behavior and medications is essential in suspected IGM, given the association with hyperprolactinemia.

Because IGM is rare, there are no randomized, placebo-controlled trials of treatment efficacy. In many cases, patients undergo complete mastectomy, which is curative but may be psychologically and physically impactful in young women. In some cases, high-dose corticosteroids have been successful; however, because the IGM process can last longer than 2 years, patients treated in this manner are exposed to steroid morbidities.¹

We report 3 cases of IGM that add to the literature on possible contributing factors, clinical presentations, and treatments for this disease. We also demonstrate that appropriate trigger identification and steroid-sparing agents, specifically methotrexate, can be breast-saving as they can alleviate this debilitating condition, obviating the need for radical surgical intervention.

CASE REPORTS 

Patient 1

A 40-year-old woman with a 4-year history of breastfeeding noted a grape-sized nodule on the left breast that grew to the size of a grapefruit after 2 weeks. Ulceration and drainage periodically occurred, forming pink plaques along the lateral aspects of the breast after healing. Her primary care provider suspected infectious mastitis; she was given an oral antibiotic (cephalexin) and intravenous antibiotics without improvement.

Imaging
Subsequent magnetic resonance imaging revealed a large, irregular, enhancing mass within the outer left breast (6.5 cm at greatest dimension) with additional surrounding amorphous enhancement highly suspicious for malignancy. There also were multiple prominent left axillary lymph nodes, with the largest demonstrating a cortical thickness of 8 mm.

Biopsy
Core breast biopsy showed benign tissue with fat necrosis. Fine-needle aspiration revealed few benign ductal cells and rare histiocytes; because these findings were nondiagnostic and cancer was still a consideration, the patient underwent excisional biopsy.

Histologic sections of breast tissue showed extensive lobulocentric inflammation comprising histiocytes and lymphocytes, with neutrophils admixed and forming microabscesses (Figure 1A). Multinucleated giant cells and single-cell necrosis were seen, but true caseous necrosis was absent (Figure 1B). Duct spaces often contained inflammatory cells or secretions. Special stains for fungal and acid-fast bacterial microorganisms were negative.

Granulomatous lobular mastitis was diagnosed, and the patient was referred to dermatology. On presentation to dermatology, the left breast showed a 6-cm area of firm induration and overlying peau d’orange change to the epidermis (Figure 2A). Based on pathologic analysis, she was worked up for a possible granulomatous etiology. Negative purified protein derivative (tuberculin)(PPD) and a normal chest radiograph ruled out tuberculosis. Normal chest radiography, serum Ca²⁺ and angiotensin-converting enzyme (ACE) levels, and ophthalmology examination ruled out sarcoidosis.

The patient reported she continued breastfeeding her 4-year-old son. Additionally, she had been started on trazadone and buspirone for alcohol abuse recovery, then switched to and maintained on fluoxetine 1 year before developing these symptoms.

Buspirone, fluoxetine, and prolonged breastfeeding all contribute to hyperprolactinemia, a possible trigger of IGM. The patient was therefore advised to stop breastfeeding and to be switched from fluoxetine to a medication that would not increase the prolactin level. She did not require methotrexate treatment because her condition resolved rapidly after breastfeeding and fluoxetine were discontinued (Figure 2B).

Patient 2 

A 40-year-old woman with no history of breastfeeding who gave birth 4.5 years prior presented to her primary care provider with a painful breast lump and rash on the right breast of 2 months’ duration. Infectious mastitis was suspected; she was given cephalexin and clindamycin without improvement of symptoms.

Imaging
Mammography and ultrasonography were nondiagnostic.

Biopsy
Breast biopsy showed tissue with large expanses of histiocytes, neutrophils, lymphocytes, plasma cells, and multinucleated giant cells (Figure 3A). Many discrete granulomas were seen against this mixed inflammatory background, associated with focal fat necrosis (Figure 3B). Special stains were negative for microorganisms. Histologic findings were consistent with granulomatous mastitis.

On presentation to dermatology, the patient was worked up for a possible granulomatous etiology, which included a negative PPD, as well as a normal chest radiograph, serum Ca²⁺ and ACE levels, and ophthalmology examination. Review of symptoms (ROS),medical history, and medication review were unremarkable.

By exclusion, the patient was given a diagnosis of IGM and started on methotrexate (15 mg weekly) with folic acid (1 mg daily). The condition of the right breast improved within 4 weeks of starting methotrexate; however, methotrexate was increased to 30 mg weekly because of occasional flares. The patient remained on methotrexate without further IGM flares for 8 months compared to prior unremitting pain and drainage. She was then tapered from methotrexate over 6 weeks without additional flares.

A 27-year-old woman who gave birth 2 years prior and discontinued breastfeeding 6 weeks after delivery noted bilateral breast rashes for several months. The lesions were growing in size, tender, and draining. Her primary care provider suspected infectious mastitis and prescribed antibiotics, which were ineffective.

Biopsy
Breast core biopsy showed histologic findings similar to patients 1 and 2, including lobulocentric mixed inflammation, neutrophilic microabscesses, and scattered discrete granulomas. Microorganisms were not found using special stains. Breast cancer was ruled out, and granulomatous mastitis was diagnosed.

Referral to Dermatology
Two years earlier, the patient tested positive for latent tuberculosis and was prescribed a 9-month regimen of isoniazid. At the current presentation, she did not have symptoms of active tuberculosis on ROS (ie, no cough, hemoptysis, weight loss, night sweats); a chest radiograph was normal. Additionally, serum Ca²⁺ and ACE levels as well as an ophthalmology examination were normal, and she was not taking any medications known to increase the prolactin level.

The patient was started on methotrexate (12.5 mg weekly) and folic acid (1 mg daily). She had 1 IGM flare and was given a tapering regimen of prednisone. She received methotrexate for 14 months, tapered during the final 3 months. She has been off methotrexate for 3 years without IGM flares and appears to be in complete remission.

COMMENT

We report 3 cases of IGM, which contribute to the literature on possible presentations, causes, and conservative treatment of this rare connective-tissue disorder.

Differential Diagnosis

The time between recognition of symptoms and diagnosis and treatment of IGM often is prolonged because IGM can present similarly to other disorders, such as infection, breast cancer, tuberculosis, and sarcoidosis. Idiopathic granulomatous mastitis is a diagnosis of exclusion, made after obtaining evidence of granulomatous inflammation on breast biopsy and ruling out other granulomatous disorders, such as tuberculosis and sarcoidosis (Table 1).^3,4

Tuberculosis
A full ROS and a PPD test or T-SPOT.TB test can be helpful in ruling out tuberculosis; because anergy occurs in some patients, tuberculosis should be evaluated in the context of known immunosuppression or human immunodeficiency virus status, or in the case of miliary tuberculosis.

Chest radiography findings classically showing upper lobe infiltrates with cavities in active tuberculosis also should be sought.³ Ziehl-Neelsen staining of 2 sputum specimens, assessed by conventional light microscopy at the time of tissue biopsy has 64% sensitivity and 98% specificity for detecting Mycobacterium tuberculosis; auramine O staining, examined with light-emitting diode fluorescence microscopy, has 73% sensitivity and 93% specificity.⁵

Sarcoidosis
Because more than 90% of sarcoid patients have lung disease, a chest radiograph is used to screen for hilar lymphadenopathy.³ An elevated serum ACE level also can be helpful in diagnosis, but patients do not always have increased ACE, which can occur in other diseases, such as hyperthyroidism and miliary tuberculosis. Sarcoid granulomas can increase active vitamin D production, which in turn increases serum Ca²⁺ in 10% of sarcoid patients. Last, an ophthalmology evaluation should be obtained to rule out anterior or posterior uveitis that can occur in sarcoidosis and initially remain asymptomatic.³ Once these other causes of granulomatous inflammation have been ruled out, a diagnosis of IGM can be made.

Prolactinoma
Prolactinoma is an important cause of hyperprolactinemia that can be screened for based on ROS and the serum prolactin level. Prolactinoma can cause oligomenorrhea or amenorrhea and galactorrhea in 90% and 80% of premenopausal women, respectively, as well as erectile dysfunction and decreased libido in men. Infertility, headache, and visual impairment may be experienced in both sexes.⁴

A normal prolactin level is less than 25 μg/L; more than 25 μg/L but less than 100 μg/L usually is due to certain drugs (eTable),^6-11 estrogen, or idiopathic reasons; and more than 150 μg/L usually is due to prolactinoma.⁵ In many cases, removal of hyperprolactinemia-precipitating factors can resolve disease, as in patient 1. If symptoms continue or precipitating factors are absent, IGM symptom-based treatment should be administered.

Course and Management

Idiopathic granulomatous mastitis is self-limited and usually resolves within 2 years. Therefore, the goal of treatment is to suppress associated pain and drainage until the active inflammatory phase of IGM self-resolves. An established protocol for treating IGM does not exist, but common treatments include corticosteroids, methotrexate, and limited or wide surgical excision (Table 2).^12-16 Before beginning any of these treatments, IGM triggers, such as breastfeeding and drugs that induce hyperprolactinemia, should be removed.

It is important to consider which treatment option is best for limiting disease recurrence and adverse effects (AEs). Keep in mind that the available data are limited, as there are no randomized controlled trials looking at these treatments. Nevertheless, we recommend methotrexate as first line because it resolves granulomatous inflammation symptoms without invasive surgery, while limiting corticosteroid AEs.¹²

With or without concurrent use of corticosteroids, surgical excision typically is the mainstay of treatment. However, surgical excision of IGM lesions can be complicated by abscess formation, fistula, and chronic pyogenic secretions, in addition to a 5% to 50% rate of recurrence of disease.^12-14 Limited excision often is insufficient; therefore, wide local excision, in which negative margins around granulomatous inflammation are obtained, is the surgical modality of choice.¹⁴ Wide local excision can be disfiguring to the breast in young women affected by IGM, making it an undesirable treatment option.

Corticosteroids often have been used to treat IGM, but their efficacy is variable, symptoms can recur upon drug removal, and remarkable AEs can result from long-term use.¹² Additionally, corticosteroid therapy often is used in combination with excision, making it difficult to determine the extent to which corticosteroids or excision are more beneficial. In a prospective observational study, corticosteroid therapy alone resolved 80% of IGM symptoms after 159 days on average. After complete symptom resolution, 23% of patients had disease recurrence.⁹ Observed AEs included gastritis, weight gain, osteoporosis, glucose intolerance, and Cushing syndrome.^12,15

Methotrexate for IGM has not been reviewed in a randomized controlled trial; case reports have shown 83% symptom resolution, with 17% recurrence and limited long-term AEs.¹² Because the active phase of IGM can persist for 2 years, immunosuppressive therapy with limited AEs is necessary. Many AEs can occur when high-dose methotrexate is given for cancer treatment. Low-dose methotrexate has been extensively studied in long-term treatment of rheumatoid arthritis. Adverse effects may include gastrointestinal tract upset and hepatic dysfunction, which are limited when given with folic acid.

Regardless of folic acid cotreatment, stomatitis may occur. Women should use an effective method of birth control because severe birth defects may occur on even low-dose methotrexate.¹⁶

Compared to corticosteroid or surgical treatment, we recommend low-dose methotrexate therapy based on its high efficacy with limited AEs. An occasional mild flare of IGM symptoms with methotrexate is not unusual. If it occurs, corticosteroids can be added and tapered for as long as 2 weeks to speed up resolution of flares while reducing long-term AEs of corticosteroids.

Surgical excision can be performed in cases refractory to all systemic therapies.

CONCLUSION

Idiopathic granulomatous mastitis is a rare granulomatous breast disorder that can have a prolonged time to diagnosis, delaying proper treatment. Many cases self-resolve, but more severe cases can persist for a long period before adequate symptomatic treatment is achieved by methotrexate, corticosteroids, or surgical excision. Before using these therapies, it is important to identify and remove contributing factors, such as long-term breastfeeding and drugs that induce hyperprolactinemia. Improving the rate of IGM diagnosis and treatment would greatly benefit these patients. We report 1 case in which removal of possible precipitating IGM factors led to symptom resolution and 2 cases in which methotrexate was an effective IGM treatment that limited the need for invasive procedures and corticosteroid AEs.

En coup de sabre (ECDS) is a rare subtype of linear scleroderma that is limited to the hemiface in a unilateral distribution. The lesional skin first exhibits contraction and stiffness that lead to characteristic fibrotic plaques with associated linear alopecia.¹ The pansclerotic plaques are ivory in color with hyperpigmented to violaceous borders extending as a paramedian band on the frontoparietal scalp.^2,3 The skin lesions bear resemblance to the stroke of the sabre sword, giving the condition its unique name. Many patients initially present with concerns of frontal scalp alopecia.³ Linear morphea, including the ECDS subtype, is predominantly seen in children and women, usually presenting within the first 2 decades of life.^1,4

The differential diagnoses of ECDS include focal dermal hypoplasia, steroid atrophy, localized morphea, and lupus profundus.⁵ En coup de sabre should be distinguished from progressive hemifacial atrophy (PHA)(also known as Parry-Romberg syndrome).⁶ Progressive hemifacial atrophy presents as unilateral atrophy of the face involving skin, subcutaneous tissue, muscle, and underlying bone in the distribution of the trigeminal nerve.¹ Both PHA and ECDS exist on a spectrum of linear scleroderma and may coexist in the same patient.⁶

There is a strong association with extracutaneous neurologic involvement, including seizures, ocular abnormalities, trigeminal neuralgia, and headache.^7-10 One study examining ECDS and PHA demonstrated that 44% (19/43) of patients who underwent central nervous system imaging had abnormal findings.¹¹ The majority of patients had magnetic resonance imaging with or without contrast, computed tomography, or both. The most common findings on T2-weighted images were white matter hyperintensities, mostly in subcortical and periventricular regions. The findings were bilateral in 61% (11/18) of patients and ipsilateral to the lesion in 33% (6/18) of patients.¹¹ We present a case of ECDS masquerading as alopecia in a 77-year-old woman.

Case Report

A 77-year-old white woman presented with a chief concern of hair loss on the scalp that had been present since 12 years of age. During her adult life, the scalp lesion remained unchanged with no associated symptoms. Her medical history was remarkable for hypertension and non–insulin-dependent diabetes mellitus. The patient denied any history of seizure disorders, facial paralysis, or neurologic deficits. Physical examination revealed a 13.6-cm linear, alopecic, hyperpigmented plaque extending from the left forehead and temporal scalp to the posterior occipital scalp with notable loss of underlying subcutaneous tissue (Figure). The left temporal scalp and forehead demonstrated pronounced atrophy with overlying telangiectases. Minimal depression was observed in the temporal scalp and forehead. The left cranial bone was easily palpable with no underlying subcutaneous tissue present. Computed tomography of the brain revealed no underlying skull or soft tissue abnormalities. No treatment was initiated, as the lesion was of minimal concern to the patient.

Comment

Etiology and Presentation                                                                                                                                                                                                                                      
En coup de sabre is a rare subtype of linear morphea that involves the frontoparietal scalp and forehead.^7,12,13 It manifests as a solitary, linear, fibrous plaque that involves the skin, underlying muscle, and bone.⁷ Although most cases present with a single lesion, multiple lesions can occur.⁸ The exact etiology of this disease remains to be determined but is characterized by thickening and hardening of the skin secondary to increased collagen production.⁷ The incidence of linear morphea ranges from 0.4 to 2.7 cases per 100,000 individuals and is more prevalent in white patients and women.¹⁴ Linear morphea is commonly found in children. Children are more likely to have linear morphea on the face, which can lead to lifelong disfigurement.² Although the disease peaks in the fourth decade of life for adults, most pediatric cases are diagnosed between 2 and 14 years of age.^14-16

Pathogenesis                                                                                                                                                                                                                                                       
Clinical and histopathological data suggest that a complex interaction among the vasculature, extracellular matrix, and immune system plays a role in the pathogenesis of the disease. Similar to scleroderma, the CD4 helper T cell may be involved in the fibrotic changes that occur within these lesions.¹⁷ Early in the disease process, T_H1 and T_H17 inflammatory pathways predominate. The late fibrotic changes seen in scleroderma are more associated with a shift to the T_H2 inflammatory pathway.¹⁷ Infection with Borrelia burgdorferi has been implicated abroad, but a large-scale study confirming Borrelia as a pathologic factor within morphea lesions has not been completed to date.^18-20 Some authors believe early lesions of ECDS mimic erythema chronica migrans, with the late lesions resembling acrodermatitis chronica atrophicans.²⁰

Histopathology                                                                                                                                                                                                                                     
Histopathologic findings of morphea tend to vary depending on the stage of the disease. The 2 stages of morphea can be differentiated by the degree of inflammation present histologically.^14,21 The early phase of morphea primarily affects the connective and subcutaneous tissue surrounding eccrine sweat glands.^14,21 A dense dermal and subcutaneous perivascular lymphocytic infiltrate with a mixture of lymphocytes, plasma cells, and histiocytes is commonly observed.⁵ Later stages of the disease demonstrate densely packed homogenous collagen with minimal inflammation and loss of eccrine glands and blood vessels.^14,21 The adipose tissue is generally replaced by sclerotic collagen, giving the biopsy a squared-off appearance.^5,14

Management                                                                                                                                                                                                                                                            
En coup de sabre presents a treatment challenge. In active lesions, topical or intralesional corticosteroids are considered treatment of choice.⁵ Methotrexate has proven useful in the treatment of acute and deep forms of linear morphea. A study examining methotrexate in juvenile localized scleroderma, with the majority of patients having the linear subtype, revealed that methotrexate is both efficacious and well tolerated.²² Other reports in the literature reveal efficacy with the use of intravenous corticosteroids and methotrexate combination therapy for treatment of morphea.^23,24 A longitudinal prospective study examining the use of high-dose methotrexate and oral corticosteroids for the treatment of localized scleroderma yielded positive results, with patients showing clinical improvement within 2 months of initiation of combination therapy.²⁵ Other treatments include excimer laser; calcipotriene and tacrolimus; and surgical approaches such as autologous fat grafting, grafting with muscle flaps, and tissue inserts.^21,26-31 In addition, patients can choose to forego therapy, as was the case with our patient.

Conclusion

En coup de sabre is a rare subtype of linear scleroderma that is limited to the ipsilateral scalp and face predominately in children and women. Neurologic involvement is common and should prompt a comprehensive neurologic workup in patients suspected to have ECDS or PHA. Current treatment recommendations include topical, intralesional, and oral corticosteroids; methotrexate; and surgical grafts. Although ECDS is a rare entity, more intensive research is needed on the exact pathophysiology and effective treatment options that focus on improving the cosmetic outcome in these patients. Cosmesis is the primary concern in patients with ECDS and should be managed early and appropriately to prevent long-term psychological sequelae.

En coup de sabre (ECDS) is a rare subtype of linear scleroderma that is limited to the hemiface in a unilateral distribution. The lesional skin first exhibits contraction and stiffness that lead to characteristic fibrotic plaques with associated linear alopecia.¹ The pansclerotic plaques are ivory in color with hyperpigmented to violaceous borders extending as a paramedian band on the frontoparietal scalp.^2,3 The skin lesions bear resemblance to the stroke of the sabre sword, giving the condition its unique name. Many patients initially present with concerns of frontal scalp alopecia.³ Linear morphea, including the ECDS subtype, is predominantly seen in children and women, usually presenting within the first 2 decades of life.^1,4

The differential diagnoses of ECDS include focal dermal hypoplasia, steroid atrophy, localized morphea, and lupus profundus.⁵ En coup de sabre should be distinguished from progressive hemifacial atrophy (PHA)(also known as Parry-Romberg syndrome).⁶ Progressive hemifacial atrophy presents as unilateral atrophy of the face involving skin, subcutaneous tissue, muscle, and underlying bone in the distribution of the trigeminal nerve.¹ Both PHA and ECDS exist on a spectrum of linear scleroderma and may coexist in the same patient.⁶

There is a strong association with extracutaneous neurologic involvement, including seizures, ocular abnormalities, trigeminal neuralgia, and headache.^7-10 One study examining ECDS and PHA demonstrated that 44% (19/43) of patients who underwent central nervous system imaging had abnormal findings.¹¹ The majority of patients had magnetic resonance imaging with or without contrast, computed tomography, or both. The most common findings on T2-weighted images were white matter hyperintensities, mostly in subcortical and periventricular regions. The findings were bilateral in 61% (11/18) of patients and ipsilateral to the lesion in 33% (6/18) of patients.¹¹ We present a case of ECDS masquerading as alopecia in a 77-year-old woman.

Case Report

A 77-year-old white woman presented with a chief concern of hair loss on the scalp that had been present since 12 years of age. During her adult life, the scalp lesion remained unchanged with no associated symptoms. Her medical history was remarkable for hypertension and non–insulin-dependent diabetes mellitus. The patient denied any history of seizure disorders, facial paralysis, or neurologic deficits. Physical examination revealed a 13.6-cm linear, alopecic, hyperpigmented plaque extending from the left forehead and temporal scalp to the posterior occipital scalp with notable loss of underlying subcutaneous tissue (Figure). The left temporal scalp and forehead demonstrated pronounced atrophy with overlying telangiectases. Minimal depression was observed in the temporal scalp and forehead. The left cranial bone was easily palpable with no underlying subcutaneous tissue present. Computed tomography of the brain revealed no underlying skull or soft tissue abnormalities. No treatment was initiated, as the lesion was of minimal concern to the patient.

Comment

Etiology and Presentation                                                                                                                                                                                                                                      
En coup de sabre is a rare subtype of linear morphea that involves the frontoparietal scalp and forehead.^7,12,13 It manifests as a solitary, linear, fibrous plaque that involves the skin, underlying muscle, and bone.⁷ Although most cases present with a single lesion, multiple lesions can occur.⁸ The exact etiology of this disease remains to be determined but is characterized by thickening and hardening of the skin secondary to increased collagen production.⁷ The incidence of linear morphea ranges from 0.4 to 2.7 cases per 100,000 individuals and is more prevalent in white patients and women.¹⁴ Linear morphea is commonly found in children. Children are more likely to have linear morphea on the face, which can lead to lifelong disfigurement.² Although the disease peaks in the fourth decade of life for adults, most pediatric cases are diagnosed between 2 and 14 years of age.^14-16

Pathogenesis                                                                                                                                                                                                                                                       
Clinical and histopathological data suggest that a complex interaction among the vasculature, extracellular matrix, and immune system plays a role in the pathogenesis of the disease. Similar to scleroderma, the CD4 helper T cell may be involved in the fibrotic changes that occur within these lesions.¹⁷ Early in the disease process, T_H1 and T_H17 inflammatory pathways predominate. The late fibrotic changes seen in scleroderma are more associated with a shift to the T_H2 inflammatory pathway.¹⁷ Infection with Borrelia burgdorferi has been implicated abroad, but a large-scale study confirming Borrelia as a pathologic factor within morphea lesions has not been completed to date.^18-20 Some authors believe early lesions of ECDS mimic erythema chronica migrans, with the late lesions resembling acrodermatitis chronica atrophicans.²⁰

Histopathology                                                                                                                                                                                                                                     
Histopathologic findings of morphea tend to vary depending on the stage of the disease. The 2 stages of morphea can be differentiated by the degree of inflammation present histologically.^14,21 The early phase of morphea primarily affects the connective and subcutaneous tissue surrounding eccrine sweat glands.^14,21 A dense dermal and subcutaneous perivascular lymphocytic infiltrate with a mixture of lymphocytes, plasma cells, and histiocytes is commonly observed.⁵ Later stages of the disease demonstrate densely packed homogenous collagen with minimal inflammation and loss of eccrine glands and blood vessels.^14,21 The adipose tissue is generally replaced by sclerotic collagen, giving the biopsy a squared-off appearance.^5,14

Management                                                                                                                                                                                                                                                            
En coup de sabre presents a treatment challenge. In active lesions, topical or intralesional corticosteroids are considered treatment of choice.⁵ Methotrexate has proven useful in the treatment of acute and deep forms of linear morphea. A study examining methotrexate in juvenile localized scleroderma, with the majority of patients having the linear subtype, revealed that methotrexate is both efficacious and well tolerated.²² Other reports in the literature reveal efficacy with the use of intravenous corticosteroids and methotrexate combination therapy for treatment of morphea.^23,24 A longitudinal prospective study examining the use of high-dose methotrexate and oral corticosteroids for the treatment of localized scleroderma yielded positive results, with patients showing clinical improvement within 2 months of initiation of combination therapy.²⁵ Other treatments include excimer laser; calcipotriene and tacrolimus; and surgical approaches such as autologous fat grafting, grafting with muscle flaps, and tissue inserts.^21,26-31 In addition, patients can choose to forego therapy, as was the case with our patient.

Conclusion

En coup de sabre is a rare subtype of linear scleroderma that is limited to the ipsilateral scalp and face predominately in children and women. Neurologic involvement is common and should prompt a comprehensive neurologic workup in patients suspected to have ECDS or PHA. Current treatment recommendations include topical, intralesional, and oral corticosteroids; methotrexate; and surgical grafts. Although ECDS is a rare entity, more intensive research is needed on the exact pathophysiology and effective treatment options that focus on improving the cosmetic outcome in these patients. Cosmesis is the primary concern in patients with ECDS and should be managed early and appropriately to prevent long-term psychological sequelae.

En coup de sabre (ECDS) is a rare subtype of linear scleroderma that is limited to the hemiface in a unilateral distribution. The lesional skin first exhibits contraction and stiffness that lead to characteristic fibrotic plaques with associated linear alopecia.¹ The pansclerotic plaques are ivory in color with hyperpigmented to violaceous borders extending as a paramedian band on the frontoparietal scalp.^2,3 The skin lesions bear resemblance to the stroke of the sabre sword, giving the condition its unique name. Many patients initially present with concerns of frontal scalp alopecia.³ Linear morphea, including the ECDS subtype, is predominantly seen in children and women, usually presenting within the first 2 decades of life.^1,4

The differential diagnoses of ECDS include focal dermal hypoplasia, steroid atrophy, localized morphea, and lupus profundus.⁵ En coup de sabre should be distinguished from progressive hemifacial atrophy (PHA)(also known as Parry-Romberg syndrome).⁶ Progressive hemifacial atrophy presents as unilateral atrophy of the face involving skin, subcutaneous tissue, muscle, and underlying bone in the distribution of the trigeminal nerve.¹ Both PHA and ECDS exist on a spectrum of linear scleroderma and may coexist in the same patient.⁶

There is a strong association with extracutaneous neurologic involvement, including seizures, ocular abnormalities, trigeminal neuralgia, and headache.^7-10 One study examining ECDS and PHA demonstrated that 44% (19/43) of patients who underwent central nervous system imaging had abnormal findings.¹¹ The majority of patients had magnetic resonance imaging with or without contrast, computed tomography, or both. The most common findings on T2-weighted images were white matter hyperintensities, mostly in subcortical and periventricular regions. The findings were bilateral in 61% (11/18) of patients and ipsilateral to the lesion in 33% (6/18) of patients.¹¹ We present a case of ECDS masquerading as alopecia in a 77-year-old woman.

Case Report

A 77-year-old white woman presented with a chief concern of hair loss on the scalp that had been present since 12 years of age. During her adult life, the scalp lesion remained unchanged with no associated symptoms. Her medical history was remarkable for hypertension and non–insulin-dependent diabetes mellitus. The patient denied any history of seizure disorders, facial paralysis, or neurologic deficits. Physical examination revealed a 13.6-cm linear, alopecic, hyperpigmented plaque extending from the left forehead and temporal scalp to the posterior occipital scalp with notable loss of underlying subcutaneous tissue (Figure). The left temporal scalp and forehead demonstrated pronounced atrophy with overlying telangiectases. Minimal depression was observed in the temporal scalp and forehead. The left cranial bone was easily palpable with no underlying subcutaneous tissue present. Computed tomography of the brain revealed no underlying skull or soft tissue abnormalities. No treatment was initiated, as the lesion was of minimal concern to the patient.

Comment

Etiology and Presentation                                                                                                                                                                                                                                      
En coup de sabre is a rare subtype of linear morphea that involves the frontoparietal scalp and forehead.^7,12,13 It manifests as a solitary, linear, fibrous plaque that involves the skin, underlying muscle, and bone.⁷ Although most cases present with a single lesion, multiple lesions can occur.⁸ The exact etiology of this disease remains to be determined but is characterized by thickening and hardening of the skin secondary to increased collagen production.⁷ The incidence of linear morphea ranges from 0.4 to 2.7 cases per 100,000 individuals and is more prevalent in white patients and women.¹⁴ Linear morphea is commonly found in children. Children are more likely to have linear morphea on the face, which can lead to lifelong disfigurement.² Although the disease peaks in the fourth decade of life for adults, most pediatric cases are diagnosed between 2 and 14 years of age.^14-16

Pathogenesis                                                                                                                                                                                                                                                       
Clinical and histopathological data suggest that a complex interaction among the vasculature, extracellular matrix, and immune system plays a role in the pathogenesis of the disease. Similar to scleroderma, the CD4 helper T cell may be involved in the fibrotic changes that occur within these lesions.¹⁷ Early in the disease process, T_H1 and T_H17 inflammatory pathways predominate. The late fibrotic changes seen in scleroderma are more associated with a shift to the T_H2 inflammatory pathway.¹⁷ Infection with Borrelia burgdorferi has been implicated abroad, but a large-scale study confirming Borrelia as a pathologic factor within morphea lesions has not been completed to date.^18-20 Some authors believe early lesions of ECDS mimic erythema chronica migrans, with the late lesions resembling acrodermatitis chronica atrophicans.²⁰

Histopathology                                                                                                                                                                                                                                     
Histopathologic findings of morphea tend to vary depending on the stage of the disease. The 2 stages of morphea can be differentiated by the degree of inflammation present histologically.^14,21 The early phase of morphea primarily affects the connective and subcutaneous tissue surrounding eccrine sweat glands.^14,21 A dense dermal and subcutaneous perivascular lymphocytic infiltrate with a mixture of lymphocytes, plasma cells, and histiocytes is commonly observed.⁵ Later stages of the disease demonstrate densely packed homogenous collagen with minimal inflammation and loss of eccrine glands and blood vessels.^14,21 The adipose tissue is generally replaced by sclerotic collagen, giving the biopsy a squared-off appearance.^5,14

Management                                                                                                                                                                                                                                                            
En coup de sabre presents a treatment challenge. In active lesions, topical or intralesional corticosteroids are considered treatment of choice.⁵ Methotrexate has proven useful in the treatment of acute and deep forms of linear morphea. A study examining methotrexate in juvenile localized scleroderma, with the majority of patients having the linear subtype, revealed that methotrexate is both efficacious and well tolerated.²² Other reports in the literature reveal efficacy with the use of intravenous corticosteroids and methotrexate combination therapy for treatment of morphea.^23,24 A longitudinal prospective study examining the use of high-dose methotrexate and oral corticosteroids for the treatment of localized scleroderma yielded positive results, with patients showing clinical improvement within 2 months of initiation of combination therapy.²⁵ Other treatments include excimer laser; calcipotriene and tacrolimus; and surgical approaches such as autologous fat grafting, grafting with muscle flaps, and tissue inserts.^21,26-31 In addition, patients can choose to forego therapy, as was the case with our patient.

Conclusion

En coup de sabre is a rare subtype of linear scleroderma that is limited to the ipsilateral scalp and face predominately in children and women. Neurologic involvement is common and should prompt a comprehensive neurologic workup in patients suspected to have ECDS or PHA. Current treatment recommendations include topical, intralesional, and oral corticosteroids; methotrexate; and surgical grafts. Although ECDS is a rare entity, more intensive research is needed on the exact pathophysiology and effective treatment options that focus on improving the cosmetic outcome in these patients. Cosmesis is the primary concern in patients with ECDS and should be managed early and appropriately to prevent long-term psychological sequelae.

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

Bedbugs are common pests causing several health and economic consequences. With increased travel, pesticide resistance, and a lack of awareness about prevention, bedbugs have become even more difficult to control, especially within large population centers.¹ The US Environmental Protection Agency considers bedbugs to be a considerable public health issue.² Typically, they are found in private residences; however, there have been more reports of bedbugs discovered in the workplace within the last 20 years.^3-5 Herein, we present a case of bedbugs presenting in this unusual environment.

Case Report

A 42-year-old man presented to our dermatology clinic with intensely itchy bumps over the bilateral posterior arms of 3 months’ duration. He had no other skin, hair, or nail concerns. Over the last 3 months prior to dermatologic evaluation, he was treated by an outside physician with topical steroids, systemic antibiotics, topical antifungals, and even systemic steroids with no improvement of the lesions or symptoms. On clinical examination at the current presentation, 8 to 10 pink dermal papules coalescing into 10-cm round patches were noted on the bilateral posterior arms (Figure 1). A punch biopsy of the posterior right arm was performed, and histologic analysis showed a dense superficial and deep infiltrate and a perivascular infiltrate of lymphocytes and eosinophils (Figure 2). No notable epidermal changes were observed.

At this time, the patient was counseled that the most likely cause was some unknown arthropod exposure. Given the chronicity of the patient’s disease course, bedbugs were favored; however, an extensive search of the patient’s home failed to uncover any arthropods, let alone bedbugs. A few weeks later, the patient discovered insects emanating from the mesh backing of his office chair while at work (Figure 3). The location of the intruders corresponded exactly with the lesions on the posterior arms. The occupational health office at his workplace collected samples of the arthropods and confirmed they were bedbugs. The patient’s lesions resolved with topical clobetasol once eradication of the workplace was complete.

Morphology and Epidemiology
Bedbugs are wingless arthropods that have flat, oval-shaped, reddish brown bodies. They are approximately 4.5-mm long and 2.5-mm wide (Figure 4). The 2 most common species of bedbugs that infect humans are Cimex lectularius and Cimex hemipterus. Bedbugs are most commonly found in hotels, apartments, and residential households near sleep locations. They reside in crevices, cracks, mattresses, cushions, dressers, and other structures proximal to the bed. During the day they remain hidden, but at night they emerge for a blood meal. The average lifespan of a bedbug is 6 to 12 months.⁶ Females lay more than 200 eggs that hatch in approximately 6 to 10 days.⁷ Bedbugs progress through 5 nymph stages before becoming adults; several blood meals are required to advance each stage.⁶

Although commonly attributed to the home, bedbugs are being increasingly seen in the office setting.^3-5 In a survey given to pest management professionals in 2015, more than 45% reported that they were contracted by corporations for bedbug infestations in office settings, an increase from 18% in 2010 and 36% in 2013.³ Bedbugs are brought into offices through clothing, luggage, books, and other personal items. Unable to find hosts at night, bedbugs adapt to daytime hours and spread to more unpredictable locations, including chairs, office equipment, desks, and computers.⁴ Additionally, they frequently move around to find a suitable host.⁵ As a result, the growth rate of bedbugs in an office setting is much slower than in the home, with fewer insects. Our patient did not have bedbugs at home, but it is possible that other employees transported them to the office over time.

Clinical Manifestations
Bedbugs cause pruritic and nonpruritic skin rashes, often of the arms, legs, neck, and face. A common reaction is an erythematous papule with a hemorrhagic punctum caused by one bite.⁸ Other presentations include purpuric macules, bullae, and papular urticaria.^8-10 Although bedbugs are suspected to transmit infectious diseases, no reports have substantiated that claim.¹¹

Our patient had several coalescing dermal papules on the arms indicating multiple bites around the same area. Due to the stationary aspect of his job—with the arms resting on his chair while typing at his desk—our patient was an easy target for consistent blood meals.

Detection
Due to an overall smaller population of insects in an office setting, detection of bedbugs in the workplace can be difficult. Infestations can be primarily identified on visual inspection by pest control.¹² The mesh backing on our patient’s chair was one site where bedbugs resided. It is important to check areas where employees congregate, such as lounges, lunch areas, conference rooms, and printers.⁴ It also is essential to examine coatracks and locker rooms, as employees may leave personal items that can serve as a source of transmission of the bugs from home. Additional detection tools provided by pest management professionals include canines, as well as devices that emit pheromones, carbon dioxide, or heat to ensnare the insects.¹²

Treatment
Treatment of bedbug bites is quite variable. For some patients, lesions may resolve on their own. Pruritic maculopapular eruptions can be treated with topical pramoxine or doxepin.⁸ Patients who develop allergic urticaria can use oral antihistamines. Systemic reactions such as anaphylaxis can be treated with a combination of intramuscular epinephrine, antihistamines, and corticosteroids.⁸ The etiology of our patient’s condition initially was unknown, and thus he was given unnecessary systemic steroids and antifungals until the source of the rash was identified and eradicated. Topical clobetasol was subsequently administered and was sufficient to resolve his symptoms.

Final Thoughts

Bedbugs continue to remain a nuisance in the home. This case provides an example of bedbugs in the office, a location that is not commonly associated with bedbug infestations. Bedbugs pose numerous psychological, economic, and health consequences.² Productivity can be reduced, as patients with symptomatic lesions will be unable to work effectively, and those who are unaffected may be unwilling to work knowing their office environment poses a health risk. In addition, employees may worry about bringing the bedbugs home. It is important that employees be educated on the signs of a bedbug infestation and take preventive measures to stop spreading or introducing them to the office space. Due to the scattered habitation of bedbugs in offices, pest control managers need to be vigilant to identify sources of infestation and eradicate accordingly. Clinical manifestations can be nonspecific, resembling autoimmune disorders, fungal infections, or bites from other various arthropods; thus, treatment is highly dependent on the patient’s history and occupational exposure.

Bedbugs have successfully adapted to a new environment in the office space. Dermatologists and other health care professionals can no longer exclusively associate bedbugs with the home. When the clinical and histological presentation suggests an arthropod assault, we must counsel our patients to surveil their homes and work settings alike. If necessary, they should seek the assistance of occupational health professionals.

The definition of warts is variable, largely reflecting their manifold appearance, biologic potential, and public health concerns. One vernacular dictionary defines warts as:

Small, benign growths caused by a vital infection of the skin or mucous membrane. The virus infects the surface layer. The viruses that cause warts are members of the human papilloma virus (HPV) family. Warts are not cancerous but some strains of HPV, usually not associated with warts, have been linked with cancer formation. Warts are contagious from person to person and from one area of the body to another on the same person.¹

The World Health Organization defines warts by their structural components as:

Human papillomavirus (HPV) is a small, non-enveloped deoxyribonucleic acid (DNA) virus that infects skin or mucosal cells. The circular, double-stranded viral genome is approximately 8-kb in length. The genome encodes for 6 early proteins responsible for virus replication and 2 late proteins, L1 and L2, which are the viral structural proteins.²

In pediatric and adolescent dermatology, warts often are defined by their location and morphology; for example, facial warts typically are flat, minimally hyperkeratotic, or filiform, wherein the base is narrow and the lesion is tall, growing at a 90° angle to the surface of the skin. On the arms and legs, warts usually present as round to oval papules with overlying thick hyperkeratosis and/or callosity.^3,4 Common warts usually are flesh colored or lighter, and heavily pigmented lesions should be evaluated dermoscopically for a pigment network and biopsied when pigment is present.⁵

In this article, a successful paradigm for management of pediatric warts is provided with enhanced outcomes based on further insight into the disease course and patient selection.

Epidemiology of Pediatric Warts

There are more than 200 types of human papillomaviruses (HPV), with more than 100 oncogenic types. There is quite a bit of homology by species and genus that contributes to cross-immunity and similar behavior between certain types of HPV. The lifetime incidence of warts is very high. Approximately 30% of children develop a wart.⁶ A review of the 2007 National Health Interview Survey of 9417 children demonstrated a steady increase in prevalence of warts from 1 to 2 years of age to 7 to 8 years of age, with a peak at 9 to 10 years of age and a plateau at 11 to 17 years of age. Warts were most common in non-Hispanic white children and less common in black children.⁷ In an in-person survey of 12,370 individuals aged 18 to 74 years from 5 European countries, warts were the most common physician-diagnosed (27.3%) and self-reported (41.0%) dermatologic condition. Warts are more common in Northern countries (eg, Netherlands, Germany).⁸ Children with atopic dermatitis have a higher risk of developing warts and extracutaneous infections. In one study, children with warts and atopic dermatitis had a higher number of infections and food allergies and higher incidence of asthma and hay fever than either condition alone.⁹

Clinical Presentation of Warts

Warts usually present as common, palmoplantar, flat, or filiform in childhood, but variations by age are common (eFigure). The common and palmoplantar variants often are caused by HPV types 1 and 2.^4,5 In infancy, vertically transmitted HPV infections can cause juvenile-onset respiratory papillomatosis or vertically transmitted condyloma. Juvenile-onset respiratory papillomatosis refers to upper respiratory papillomas that are difficult to eliminate and has been associated with exfoliated cervical cell testing with 18.1% (13/72) typed HPV-positive, which allows neonates to be exposed to HPV in the upper respiratory tract in utero.¹⁰

Vertically transmitted condyloma is a difficult topic. Much data supports the vertical transmission of condyloma as the leading cause of condyloma in small children; however, a reasonable amount of caution is needed in this patient population. In cases suspicious for sexual abuse as well as those presenting in children 4 years and older, formal household evaluation by a sexual abuse clinic and mandatory reporting is needed. Anywhere from 2.6% to 32% of cases of genital warts in children have been reported to be caused by sexual abuse.^11-13 Therefore, most investigators have recommended careful review of the patient’s history and socioeconomic circumstances as well as a thorough physical examination. Mandatory reporting of suspected child sexual abuse is required in suspicious cases. Because HPV type 16 has been found in vertically transmitted cases, concern for long-term oncogenesis exists.^11-13

Adolescents generally present with lesions on the hands and feet. Plantar warts often are caused by HPV types from the alpha genus. Subtypes noted in plantar warts include HPV types 1a, 2, 27, 57, and 65.¹⁴ By 15 years of age, genital HPV becomes a common adolescent infection, persisting into adulthood.¹⁵ When studied, genital HPV often is subclinical or latent and often is preventable through vaccination. High-risk oncogenic alpha-genus HPV types can immortalize human keratinocytes. When HPV types 11, 16, 18, and 31 are compared, HPV-18 has the highest oncogenic potential based on colony-stimulating potential.¹⁶ Vaccination with the 9-valent HPV vaccine is recommended in adolescence due to the concern for exposures to both low-potential (HPV types 6 and 11) and high-potential (HPV types 16 and 18) oncogenic HPV types. Data strongly support the benefit of 9-valent HPV vaccination in the prevention of sexually transmitted HPV in both males and females.¹⁷

Contagion of HPV is easy due to its excellent survival of fomites on surfaces, which generally is how warts are transferred in gym or pool settings where individuals who walk barefoot in changing rooms are almost twice as likely to contract plantar warts (odds ratio, 1.97 [95% CI, 1.39%-2.79%]).¹⁸ In another case series, walking barefoot, using a swimming pool, and having a household contact with warts were the leading risk factors for contraction of warts in children younger than 13 years.¹⁹ Children often transfer warts from site to site as well as to siblings and other close contacts. Skin-to-skin contact is responsible for sexual transmission of warts, and surface transmission occurs via fomites. Entry of the virus often occurs through small breaks in the skin. Other modes of transmission include orogenital.²⁰

Therapeutic Options

Although the nuances of each available treatment for pediatric warts are beyond the scope of this article, the main core of therapy is 1 of 3 approaches: (1) observation, (2) over-the-counter salicylic acid therapy, and (3) in-office cryotherapy. Observation is an affirmed style of therapy for warts, as it is expected that two-thirds of warts will spontaneously resolve in 2 years and three-quarters will resolve in 3 years.^4,5 Condyloma in children has been responsive to therapies such as cryotherapy and imiquimod,¹³ but spontaneous clearance in 5 years has been noted in 76% of children,²¹ which is linked to development of spontaneous immune response in most individuals.

Therapies for pediatric warts are characterized according to 6 major categories: destructive; immune stimulating; immune modulating, including normalization of epithelial growth; irritant; vascular destructive; and nitric oxide releasing (eTable).

Immune-Stimulating Therapies                                                                                                                                                                                                                         
Immune stimulants often are used to treat warts in children and adolescents who have many lesions, a prolonged disease course, disfigurement, and/or subungual localizations, as well as in those who have been treated with multiple destructive methods without success. Topical imiquimod and oral cimetidine are readily available, while squaric acid (at-home or in-office therapy) and intralesional candida antigen can be used in offices that carry these agents. Topical imiquimod has been reported to achieve success in genital warts in children,¹³ with good efficacy in recalcitrant, periungual, and subungual warts when used for up to 16 weeks.³¹ In one randomized clinical trial, imiquimod cream 5% combined with salicylic acid 15% was applied to warts for 6 to 10 hours for 5 consecutive days per week versus cryotherapy with liquid nitrogen every 2 weeks for a maximum of 3 months. At the end of the study period, 81.1% (30/37) of participants treated with imiquimod and salicylic acid showed clearance of their warts versus 67.3% (33/49) of those treated with cryotherapy.³²

Oral cimetidine has been reported to be successful in treating recalcitrant warts in more than 80% of children when dosed at 30 to 40 mg/kg 3 times daily, requiring 6 to 12 weeks to achieve clearance. Side effects of oral cimetidine include many cytochrome P450 interactions; gynecomastia, which limits usage in teenaged males; and stomach upset.³⁰

Treatment of recalcitrant pediatric warts with intralesional candida antigen has been associated with side effects consistent with delayed-type hypersensitivity reactions. Injections should be administered once monthly, with a minimum of 3 cycles if not effective and up to 6 cycles where partial efficacy is noted. In a retrospective review of 220 cases, 70.9% of children showed complete clearance and 16.8% had partial response.³³ However, the treatment may be limited in children by fear of needles.

Squaric acid dibutyl ester is a universal allergen that is not mutagenic on Ames testing and causes milder allergy symptoms than the mutagenic dinitrochlorobenzene and less erythema and pruritus than diphencyclopropenone. Squaric acid dibutyl ester home therapy was evaluated in 61 children with at least one nonfacial wart.³⁴ Application began with squaric acid dibutyl ester in acetone (SADBE) 2% sensitization on the arm followed by at-home application of SADBE 0.2% three to seven times weekly for a minimum of 2 months to determine benefit and for 3 to 4 months as needed; however, average response was 7 weeks. The average complete clearance was 58% and partial clearance was 18%. Side effects included erythema and mild itching as well as urticaria in one case.³⁴ In-office SADBE also has been evaluated in children. In a case series that included 29 children sensitized with SADBE 1% to 2% under occlusion followed by once monthly application of SADBE 0.5% to 5.0% to their warts, 69% clearance and 10% partial clearance was noted after a little more than 4 months of treatment.³⁵ One retrospective review compared combination SADBE, trichloroacetic acid (TCA), and cantharidin both alone and in combination as duos (eg, SADBE and TCA) or trios (SADBE, TCA, and cantharidin).²³ Of the 74 children whose medical charts were reviewed, the addition of pretreatment of warts with TCA 50% prior to in-office sensitization and monthly in-office application of SADBE increased treatment response to 100% with an average 2.45 months of therapy, whereas no enhancement was noted with cantharidin. Therefore, it appears that there may be enhanced immune reactivity when TCA pretreatment of warts is performed.²³

Immune-Modulating Therapies (Including Normalization of Epithelial Growth)
The most novel immunologic therapy for warts is plerixafor, an agent used to treat WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, which has been linked to heterozygous gain of function mutations in the chemokine receptor CXCR4 (located on 2q22). In WHIM syndrome, the mutated CXCR4 is more sensitive to CXCL12 activation. Plerixafor is a selective reversible antagonist that blocks the capacity of the chemokine CXCL12 to sustain the permanent activation of CXCR4.³⁷ Combination therapy with plerixafor and topical imiquimod has resulted in wart improvement in WHIM syndrome patients in a small series.³⁸

Oral isotretinoin has been described to be efficacious over placebo at a dosage of 30 mg daily for 12 weeks and can be used in teenagers but requires standard monitoring.³⁶

Nitric Oxide–Releasing Therapies                                                                                                                                                                                                                         
Nitric oxide release may increase local blood flow, thereby increasing immune response, or may have a primary mechanism of antimicrobial activity, which is why these agents have been investigated for wart treatment. Topical garlic has been described anecdotally as a therapy for thin childhood warts with the putative mechanism being nitric oxide release.⁴² A new investigational drug recently has had phase 2 data published. Berdazimer sodium plus carboxymethyl cellulose hydrogel has demonstrated benefit in adult warts, but data in children is lacking.⁴¹

Therapeutic Ladder for Childhood Warts

The therapeutic ladder (Table) for childhood warts starts with first doing no harm. Although many parents are disturbed by their child’s condition, the natural history of resolution is spontaneous and therefore no therapy is required in many cases. The child and his/her caregivers should be engaged to determine if he/she is emotionally disturbed or uncomfortable with their lesions and to address any fears and concerns that some children may experience (eg, contagion risk, pain with ambulation, ostracism). For example, children with hand warts may report that other children will not hold their hand while in line at school. Prominent facial lesions can be particularly problematic for children due to teasing and bullying.

Conclusion

Warts are a common infection in childhood caused by the ubiquitous HPV virus. Therapeutic options abound, but most cases are either ignored or treated with over-the-counter salicylic acid or in-office cryotherapy. The decision to employ alternative therapeutic options requires agreement by the child, his/her caregiver, and the treating physician and can be tailored to suit the desires and needs of the child. Whether or not therapy is offered, spontaneous clearance is frequently seen in common warts. On the other hand, genital warts are associated with later conversion to malignancies of the genital tract; therefore, encouragement of HPV vaccination is needed in the adolescent population to best ensure long-term genital health.

The definition of warts is variable, largely reflecting their manifold appearance, biologic potential, and public health concerns. One vernacular dictionary defines warts as:

Small, benign growths caused by a vital infection of the skin or mucous membrane. The virus infects the surface layer. The viruses that cause warts are members of the human papilloma virus (HPV) family. Warts are not cancerous but some strains of HPV, usually not associated with warts, have been linked with cancer formation. Warts are contagious from person to person and from one area of the body to another on the same person.¹

The World Health Organization defines warts by their structural components as:

Human papillomavirus (HPV) is a small, non-enveloped deoxyribonucleic acid (DNA) virus that infects skin or mucosal cells. The circular, double-stranded viral genome is approximately 8-kb in length. The genome encodes for 6 early proteins responsible for virus replication and 2 late proteins, L1 and L2, which are the viral structural proteins.²

In pediatric and adolescent dermatology, warts often are defined by their location and morphology; for example, facial warts typically are flat, minimally hyperkeratotic, or filiform, wherein the base is narrow and the lesion is tall, growing at a 90° angle to the surface of the skin. On the arms and legs, warts usually present as round to oval papules with overlying thick hyperkeratosis and/or callosity.^3,4 Common warts usually are flesh colored or lighter, and heavily pigmented lesions should be evaluated dermoscopically for a pigment network and biopsied when pigment is present.⁵

In this article, a successful paradigm for management of pediatric warts is provided with enhanced outcomes based on further insight into the disease course and patient selection.

Epidemiology of Pediatric Warts

There are more than 200 types of human papillomaviruses (HPV), with more than 100 oncogenic types. There is quite a bit of homology by species and genus that contributes to cross-immunity and similar behavior between certain types of HPV. The lifetime incidence of warts is very high. Approximately 30% of children develop a wart.⁶ A review of the 2007 National Health Interview Survey of 9417 children demonstrated a steady increase in prevalence of warts from 1 to 2 years of age to 7 to 8 years of age, with a peak at 9 to 10 years of age and a plateau at 11 to 17 years of age. Warts were most common in non-Hispanic white children and less common in black children.⁷ In an in-person survey of 12,370 individuals aged 18 to 74 years from 5 European countries, warts were the most common physician-diagnosed (27.3%) and self-reported (41.0%) dermatologic condition. Warts are more common in Northern countries (eg, Netherlands, Germany).⁸ Children with atopic dermatitis have a higher risk of developing warts and extracutaneous infections. In one study, children with warts and atopic dermatitis had a higher number of infections and food allergies and higher incidence of asthma and hay fever than either condition alone.⁹

Clinical Presentation of Warts

Warts usually present as common, palmoplantar, flat, or filiform in childhood, but variations by age are common (eFigure). The common and palmoplantar variants often are caused by HPV types 1 and 2.^4,5 In infancy, vertically transmitted HPV infections can cause juvenile-onset respiratory papillomatosis or vertically transmitted condyloma. Juvenile-onset respiratory papillomatosis refers to upper respiratory papillomas that are difficult to eliminate and has been associated with exfoliated cervical cell testing with 18.1% (13/72) typed HPV-positive, which allows neonates to be exposed to HPV in the upper respiratory tract in utero.¹⁰

Vertically transmitted condyloma is a difficult topic. Much data supports the vertical transmission of condyloma as the leading cause of condyloma in small children; however, a reasonable amount of caution is needed in this patient population. In cases suspicious for sexual abuse as well as those presenting in children 4 years and older, formal household evaluation by a sexual abuse clinic and mandatory reporting is needed. Anywhere from 2.6% to 32% of cases of genital warts in children have been reported to be caused by sexual abuse.^11-13 Therefore, most investigators have recommended careful review of the patient’s history and socioeconomic circumstances as well as a thorough physical examination. Mandatory reporting of suspected child sexual abuse is required in suspicious cases. Because HPV type 16 has been found in vertically transmitted cases, concern for long-term oncogenesis exists.^11-13

Adolescents generally present with lesions on the hands and feet. Plantar warts often are caused by HPV types from the alpha genus. Subtypes noted in plantar warts include HPV types 1a, 2, 27, 57, and 65.¹⁴ By 15 years of age, genital HPV becomes a common adolescent infection, persisting into adulthood.¹⁵ When studied, genital HPV often is subclinical or latent and often is preventable through vaccination. High-risk oncogenic alpha-genus HPV types can immortalize human keratinocytes. When HPV types 11, 16, 18, and 31 are compared, HPV-18 has the highest oncogenic potential based on colony-stimulating potential.¹⁶ Vaccination with the 9-valent HPV vaccine is recommended in adolescence due to the concern for exposures to both low-potential (HPV types 6 and 11) and high-potential (HPV types 16 and 18) oncogenic HPV types. Data strongly support the benefit of 9-valent HPV vaccination in the prevention of sexually transmitted HPV in both males and females.¹⁷

Contagion of HPV is easy due to its excellent survival of fomites on surfaces, which generally is how warts are transferred in gym or pool settings where individuals who walk barefoot in changing rooms are almost twice as likely to contract plantar warts (odds ratio, 1.97 [95% CI, 1.39%-2.79%]).¹⁸ In another case series, walking barefoot, using a swimming pool, and having a household contact with warts were the leading risk factors for contraction of warts in children younger than 13 years.¹⁹ Children often transfer warts from site to site as well as to siblings and other close contacts. Skin-to-skin contact is responsible for sexual transmission of warts, and surface transmission occurs via fomites. Entry of the virus often occurs through small breaks in the skin. Other modes of transmission include orogenital.²⁰

Therapeutic Options

Although the nuances of each available treatment for pediatric warts are beyond the scope of this article, the main core of therapy is 1 of 3 approaches: (1) observation, (2) over-the-counter salicylic acid therapy, and (3) in-office cryotherapy. Observation is an affirmed style of therapy for warts, as it is expected that two-thirds of warts will spontaneously resolve in 2 years and three-quarters will resolve in 3 years.^4,5 Condyloma in children has been responsive to therapies such as cryotherapy and imiquimod,¹³ but spontaneous clearance in 5 years has been noted in 76% of children,²¹ which is linked to development of spontaneous immune response in most individuals.

Therapies for pediatric warts are characterized according to 6 major categories: destructive; immune stimulating; immune modulating, including normalization of epithelial growth; irritant; vascular destructive; and nitric oxide releasing (eTable).

Immune-Stimulating Therapies                                                                                                                                                                                                                         
Immune stimulants often are used to treat warts in children and adolescents who have many lesions, a prolonged disease course, disfigurement, and/or subungual localizations, as well as in those who have been treated with multiple destructive methods without success. Topical imiquimod and oral cimetidine are readily available, while squaric acid (at-home or in-office therapy) and intralesional candida antigen can be used in offices that carry these agents. Topical imiquimod has been reported to achieve success in genital warts in children,¹³ with good efficacy in recalcitrant, periungual, and subungual warts when used for up to 16 weeks.³¹ In one randomized clinical trial, imiquimod cream 5% combined with salicylic acid 15% was applied to warts for 6 to 10 hours for 5 consecutive days per week versus cryotherapy with liquid nitrogen every 2 weeks for a maximum of 3 months. At the end of the study period, 81.1% (30/37) of participants treated with imiquimod and salicylic acid showed clearance of their warts versus 67.3% (33/49) of those treated with cryotherapy.³²

Oral cimetidine has been reported to be successful in treating recalcitrant warts in more than 80% of children when dosed at 30 to 40 mg/kg 3 times daily, requiring 6 to 12 weeks to achieve clearance. Side effects of oral cimetidine include many cytochrome P450 interactions; gynecomastia, which limits usage in teenaged males; and stomach upset.³⁰

Treatment of recalcitrant pediatric warts with intralesional candida antigen has been associated with side effects consistent with delayed-type hypersensitivity reactions. Injections should be administered once monthly, with a minimum of 3 cycles if not effective and up to 6 cycles where partial efficacy is noted. In a retrospective review of 220 cases, 70.9% of children showed complete clearance and 16.8% had partial response.³³ However, the treatment may be limited in children by fear of needles.

Squaric acid dibutyl ester is a universal allergen that is not mutagenic on Ames testing and causes milder allergy symptoms than the mutagenic dinitrochlorobenzene and less erythema and pruritus than diphencyclopropenone. Squaric acid dibutyl ester home therapy was evaluated in 61 children with at least one nonfacial wart.³⁴ Application began with squaric acid dibutyl ester in acetone (SADBE) 2% sensitization on the arm followed by at-home application of SADBE 0.2% three to seven times weekly for a minimum of 2 months to determine benefit and for 3 to 4 months as needed; however, average response was 7 weeks. The average complete clearance was 58% and partial clearance was 18%. Side effects included erythema and mild itching as well as urticaria in one case.³⁴ In-office SADBE also has been evaluated in children. In a case series that included 29 children sensitized with SADBE 1% to 2% under occlusion followed by once monthly application of SADBE 0.5% to 5.0% to their warts, 69% clearance and 10% partial clearance was noted after a little more than 4 months of treatment.³⁵ One retrospective review compared combination SADBE, trichloroacetic acid (TCA), and cantharidin both alone and in combination as duos (eg, SADBE and TCA) or trios (SADBE, TCA, and cantharidin).²³ Of the 74 children whose medical charts were reviewed, the addition of pretreatment of warts with TCA 50% prior to in-office sensitization and monthly in-office application of SADBE increased treatment response to 100% with an average 2.45 months of therapy, whereas no enhancement was noted with cantharidin. Therefore, it appears that there may be enhanced immune reactivity when TCA pretreatment of warts is performed.²³

Immune-Modulating Therapies (Including Normalization of Epithelial Growth)
The most novel immunologic therapy for warts is plerixafor, an agent used to treat WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, which has been linked to heterozygous gain of function mutations in the chemokine receptor CXCR4 (located on 2q22). In WHIM syndrome, the mutated CXCR4 is more sensitive to CXCL12 activation. Plerixafor is a selective reversible antagonist that blocks the capacity of the chemokine CXCL12 to sustain the permanent activation of CXCR4.³⁷ Combination therapy with plerixafor and topical imiquimod has resulted in wart improvement in WHIM syndrome patients in a small series.³⁸

Oral isotretinoin has been described to be efficacious over placebo at a dosage of 30 mg daily for 12 weeks and can be used in teenagers but requires standard monitoring.³⁶

Nitric Oxide–Releasing Therapies                                                                                                                                                                                                                         
Nitric oxide release may increase local blood flow, thereby increasing immune response, or may have a primary mechanism of antimicrobial activity, which is why these agents have been investigated for wart treatment. Topical garlic has been described anecdotally as a therapy for thin childhood warts with the putative mechanism being nitric oxide release.⁴² A new investigational drug recently has had phase 2 data published. Berdazimer sodium plus carboxymethyl cellulose hydrogel has demonstrated benefit in adult warts, but data in children is lacking.⁴¹

Therapeutic Ladder for Childhood Warts

The therapeutic ladder (Table) for childhood warts starts with first doing no harm. Although many parents are disturbed by their child’s condition, the natural history of resolution is spontaneous and therefore no therapy is required in many cases. The child and his/her caregivers should be engaged to determine if he/she is emotionally disturbed or uncomfortable with their lesions and to address any fears and concerns that some children may experience (eg, contagion risk, pain with ambulation, ostracism). For example, children with hand warts may report that other children will not hold their hand while in line at school. Prominent facial lesions can be particularly problematic for children due to teasing and bullying.

Conclusion

Warts are a common infection in childhood caused by the ubiquitous HPV virus. Therapeutic options abound, but most cases are either ignored or treated with over-the-counter salicylic acid or in-office cryotherapy. The decision to employ alternative therapeutic options requires agreement by the child, his/her caregiver, and the treating physician and can be tailored to suit the desires and needs of the child. Whether or not therapy is offered, spontaneous clearance is frequently seen in common warts. On the other hand, genital warts are associated with later conversion to malignancies of the genital tract; therefore, encouragement of HPV vaccination is needed in the adolescent population to best ensure long-term genital health.

The definition of warts is variable, largely reflecting their manifold appearance, biologic potential, and public health concerns. One vernacular dictionary defines warts as:

Small, benign growths caused by a vital infection of the skin or mucous membrane. The virus infects the surface layer. The viruses that cause warts are members of the human papilloma virus (HPV) family. Warts are not cancerous but some strains of HPV, usually not associated with warts, have been linked with cancer formation. Warts are contagious from person to person and from one area of the body to another on the same person.¹

The World Health Organization defines warts by their structural components as:

Human papillomavirus (HPV) is a small, non-enveloped deoxyribonucleic acid (DNA) virus that infects skin or mucosal cells. The circular, double-stranded viral genome is approximately 8-kb in length. The genome encodes for 6 early proteins responsible for virus replication and 2 late proteins, L1 and L2, which are the viral structural proteins.²

In pediatric and adolescent dermatology, warts often are defined by their location and morphology; for example, facial warts typically are flat, minimally hyperkeratotic, or filiform, wherein the base is narrow and the lesion is tall, growing at a 90° angle to the surface of the skin. On the arms and legs, warts usually present as round to oval papules with overlying thick hyperkeratosis and/or callosity.^3,4 Common warts usually are flesh colored or lighter, and heavily pigmented lesions should be evaluated dermoscopically for a pigment network and biopsied when pigment is present.⁵

In this article, a successful paradigm for management of pediatric warts is provided with enhanced outcomes based on further insight into the disease course and patient selection.

Epidemiology of Pediatric Warts

There are more than 200 types of human papillomaviruses (HPV), with more than 100 oncogenic types. There is quite a bit of homology by species and genus that contributes to cross-immunity and similar behavior between certain types of HPV. The lifetime incidence of warts is very high. Approximately 30% of children develop a wart.⁶ A review of the 2007 National Health Interview Survey of 9417 children demonstrated a steady increase in prevalence of warts from 1 to 2 years of age to 7 to 8 years of age, with a peak at 9 to 10 years of age and a plateau at 11 to 17 years of age. Warts were most common in non-Hispanic white children and less common in black children.⁷ In an in-person survey of 12,370 individuals aged 18 to 74 years from 5 European countries, warts were the most common physician-diagnosed (27.3%) and self-reported (41.0%) dermatologic condition. Warts are more common in Northern countries (eg, Netherlands, Germany).⁸ Children with atopic dermatitis have a higher risk of developing warts and extracutaneous infections. In one study, children with warts and atopic dermatitis had a higher number of infections and food allergies and higher incidence of asthma and hay fever than either condition alone.⁹

Clinical Presentation of Warts

Warts usually present as common, palmoplantar, flat, or filiform in childhood, but variations by age are common (eFigure). The common and palmoplantar variants often are caused by HPV types 1 and 2.^4,5 In infancy, vertically transmitted HPV infections can cause juvenile-onset respiratory papillomatosis or vertically transmitted condyloma. Juvenile-onset respiratory papillomatosis refers to upper respiratory papillomas that are difficult to eliminate and has been associated with exfoliated cervical cell testing with 18.1% (13/72) typed HPV-positive, which allows neonates to be exposed to HPV in the upper respiratory tract in utero.¹⁰

Vertically transmitted condyloma is a difficult topic. Much data supports the vertical transmission of condyloma as the leading cause of condyloma in small children; however, a reasonable amount of caution is needed in this patient population. In cases suspicious for sexual abuse as well as those presenting in children 4 years and older, formal household evaluation by a sexual abuse clinic and mandatory reporting is needed. Anywhere from 2.6% to 32% of cases of genital warts in children have been reported to be caused by sexual abuse.^11-13 Therefore, most investigators have recommended careful review of the patient’s history and socioeconomic circumstances as well as a thorough physical examination. Mandatory reporting of suspected child sexual abuse is required in suspicious cases. Because HPV type 16 has been found in vertically transmitted cases, concern for long-term oncogenesis exists.^11-13

Adolescents generally present with lesions on the hands and feet. Plantar warts often are caused by HPV types from the alpha genus. Subtypes noted in plantar warts include HPV types 1a, 2, 27, 57, and 65.¹⁴ By 15 years of age, genital HPV becomes a common adolescent infection, persisting into adulthood.¹⁵ When studied, genital HPV often is subclinical or latent and often is preventable through vaccination. High-risk oncogenic alpha-genus HPV types can immortalize human keratinocytes. When HPV types 11, 16, 18, and 31 are compared, HPV-18 has the highest oncogenic potential based on colony-stimulating potential.¹⁶ Vaccination with the 9-valent HPV vaccine is recommended in adolescence due to the concern for exposures to both low-potential (HPV types 6 and 11) and high-potential (HPV types 16 and 18) oncogenic HPV types. Data strongly support the benefit of 9-valent HPV vaccination in the prevention of sexually transmitted HPV in both males and females.¹⁷

Contagion of HPV is easy due to its excellent survival of fomites on surfaces, which generally is how warts are transferred in gym or pool settings where individuals who walk barefoot in changing rooms are almost twice as likely to contract plantar warts (odds ratio, 1.97 [95% CI, 1.39%-2.79%]).¹⁸ In another case series, walking barefoot, using a swimming pool, and having a household contact with warts were the leading risk factors for contraction of warts in children younger than 13 years.¹⁹ Children often transfer warts from site to site as well as to siblings and other close contacts. Skin-to-skin contact is responsible for sexual transmission of warts, and surface transmission occurs via fomites. Entry of the virus often occurs through small breaks in the skin. Other modes of transmission include orogenital.²⁰

Therapeutic Options

Although the nuances of each available treatment for pediatric warts are beyond the scope of this article, the main core of therapy is 1 of 3 approaches: (1) observation, (2) over-the-counter salicylic acid therapy, and (3) in-office cryotherapy. Observation is an affirmed style of therapy for warts, as it is expected that two-thirds of warts will spontaneously resolve in 2 years and three-quarters will resolve in 3 years.^4,5 Condyloma in children has been responsive to therapies such as cryotherapy and imiquimod,¹³ but spontaneous clearance in 5 years has been noted in 76% of children,²¹ which is linked to development of spontaneous immune response in most individuals.

Therapies for pediatric warts are characterized according to 6 major categories: destructive; immune stimulating; immune modulating, including normalization of epithelial growth; irritant; vascular destructive; and nitric oxide releasing (eTable).

Immune-Stimulating Therapies                                                                                                                                                                                                                         
Immune stimulants often are used to treat warts in children and adolescents who have many lesions, a prolonged disease course, disfigurement, and/or subungual localizations, as well as in those who have been treated with multiple destructive methods without success. Topical imiquimod and oral cimetidine are readily available, while squaric acid (at-home or in-office therapy) and intralesional candida antigen can be used in offices that carry these agents. Topical imiquimod has been reported to achieve success in genital warts in children,¹³ with good efficacy in recalcitrant, periungual, and subungual warts when used for up to 16 weeks.³¹ In one randomized clinical trial, imiquimod cream 5% combined with salicylic acid 15% was applied to warts for 6 to 10 hours for 5 consecutive days per week versus cryotherapy with liquid nitrogen every 2 weeks for a maximum of 3 months. At the end of the study period, 81.1% (30/37) of participants treated with imiquimod and salicylic acid showed clearance of their warts versus 67.3% (33/49) of those treated with cryotherapy.³²

Oral cimetidine has been reported to be successful in treating recalcitrant warts in more than 80% of children when dosed at 30 to 40 mg/kg 3 times daily, requiring 6 to 12 weeks to achieve clearance. Side effects of oral cimetidine include many cytochrome P450 interactions; gynecomastia, which limits usage in teenaged males; and stomach upset.³⁰

Treatment of recalcitrant pediatric warts with intralesional candida antigen has been associated with side effects consistent with delayed-type hypersensitivity reactions. Injections should be administered once monthly, with a minimum of 3 cycles if not effective and up to 6 cycles where partial efficacy is noted. In a retrospective review of 220 cases, 70.9% of children showed complete clearance and 16.8% had partial response.³³ However, the treatment may be limited in children by fear of needles.

Squaric acid dibutyl ester is a universal allergen that is not mutagenic on Ames testing and causes milder allergy symptoms than the mutagenic dinitrochlorobenzene and less erythema and pruritus than diphencyclopropenone. Squaric acid dibutyl ester home therapy was evaluated in 61 children with at least one nonfacial wart.³⁴ Application began with squaric acid dibutyl ester in acetone (SADBE) 2% sensitization on the arm followed by at-home application of SADBE 0.2% three to seven times weekly for a minimum of 2 months to determine benefit and for 3 to 4 months as needed; however, average response was 7 weeks. The average complete clearance was 58% and partial clearance was 18%. Side effects included erythema and mild itching as well as urticaria in one case.³⁴ In-office SADBE also has been evaluated in children. In a case series that included 29 children sensitized with SADBE 1% to 2% under occlusion followed by once monthly application of SADBE 0.5% to 5.0% to their warts, 69% clearance and 10% partial clearance was noted after a little more than 4 months of treatment.³⁵ One retrospective review compared combination SADBE, trichloroacetic acid (TCA), and cantharidin both alone and in combination as duos (eg, SADBE and TCA) or trios (SADBE, TCA, and cantharidin).²³ Of the 74 children whose medical charts were reviewed, the addition of pretreatment of warts with TCA 50% prior to in-office sensitization and monthly in-office application of SADBE increased treatment response to 100% with an average 2.45 months of therapy, whereas no enhancement was noted with cantharidin. Therefore, it appears that there may be enhanced immune reactivity when TCA pretreatment of warts is performed.²³

Immune-Modulating Therapies (Including Normalization of Epithelial Growth)
The most novel immunologic therapy for warts is plerixafor, an agent used to treat WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, which has been linked to heterozygous gain of function mutations in the chemokine receptor CXCR4 (located on 2q22). In WHIM syndrome, the mutated CXCR4 is more sensitive to CXCL12 activation. Plerixafor is a selective reversible antagonist that blocks the capacity of the chemokine CXCL12 to sustain the permanent activation of CXCR4.³⁷ Combination therapy with plerixafor and topical imiquimod has resulted in wart improvement in WHIM syndrome patients in a small series.³⁸

Oral isotretinoin has been described to be efficacious over placebo at a dosage of 30 mg daily for 12 weeks and can be used in teenagers but requires standard monitoring.³⁶

Nitric Oxide–Releasing Therapies                                                                                                                                                                                                                         
Nitric oxide release may increase local blood flow, thereby increasing immune response, or may have a primary mechanism of antimicrobial activity, which is why these agents have been investigated for wart treatment. Topical garlic has been described anecdotally as a therapy for thin childhood warts with the putative mechanism being nitric oxide release.⁴² A new investigational drug recently has had phase 2 data published. Berdazimer sodium plus carboxymethyl cellulose hydrogel has demonstrated benefit in adult warts, but data in children is lacking.⁴¹

Therapeutic Ladder for Childhood Warts

The therapeutic ladder (Table) for childhood warts starts with first doing no harm. Although many parents are disturbed by their child’s condition, the natural history of resolution is spontaneous and therefore no therapy is required in many cases. The child and his/her caregivers should be engaged to determine if he/she is emotionally disturbed or uncomfortable with their lesions and to address any fears and concerns that some children may experience (eg, contagion risk, pain with ambulation, ostracism). For example, children with hand warts may report that other children will not hold their hand while in line at school. Prominent facial lesions can be particularly problematic for children due to teasing and bullying.

Conclusion

Warts are a common infection in childhood caused by the ubiquitous HPV virus. Therapeutic options abound, but most cases are either ignored or treated with over-the-counter salicylic acid or in-office cryotherapy. The decision to employ alternative therapeutic options requires agreement by the child, his/her caregiver, and the treating physician and can be tailored to suit the desires and needs of the child. Whether or not therapy is offered, spontaneous clearance is frequently seen in common warts. On the other hand, genital warts are associated with later conversion to malignancies of the genital tract; therefore, encouragement of HPV vaccination is needed in the adolescent population to best ensure long-term genital health.

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

The Diagnosis: Basal Cell Nevus Syndrome

Given the patient’s history of numerous basal cell carcinomas (BCCs), odontogenic keratocysts, palmar pits, and a nonhealing ulcer, the clinical presentation was highly suggestive of interdigital BCC in the setting of basal cell nevus syndrome (BCNS). A shave biopsy was performed revealing islands of basaloid cells with peripheral palisading and a retraction artifact surrounded by fibromyxoid stroma, consistent with nodular and infiltrative BCC (Figure 1).

Basal cell nevus syndrome (also known as Gorlin syndrome) is a rare neurocutaneous syndrome that manifests with multiple BCCs; palmar and plantar pits (Figure 2); central nervous system tumors; and skeletal anomalies including jaw cysts, macrocephaly, frontal bossing, and bifid ribs.¹ It is an autosomal-dominant condition caused by mutations in the PTCH1 gene, a tumor suppressor gene involved in the Hedgehog signaling pathway.² Basal cell carcinoma is the most distinctive feature of BCNS, causing notable morbidity. Tumors typically present between puberty and 35 years of age, and patients can have anywhere from a few to thousands of tumors. They rarely become locally aggressive; however, with radiation therapy, proliferation and local invasion may occur within a few years. Therefore, radiotherapy should be avoided in these patients.¹

Although the most common sites for BCCs in BCNS are the head, neck, and back, there is a higher rate of occurrence on sun-protected areas in BCNS compared to the general population.³ Our patient presented with interdigital BCC of the foot, which is an extremely rare occurrence. PubMed and Ovid searches using the terms basal cell carcinoma, BCC, foot, interdigital, and nonmelanoma skin cancer revealed only 3 cases of interdigital BCC of the foot. One case was associated with prior surgical trauma, the second presented as a junctional nevus, and the third did not appear to have any associated inciting factors.^4-6 Dermatologists need to have a low threshold for biopsy for any unusual nonhealing lesions, especially in the setting of BCNS. Basal cell carcinomas in BCNS cannot be histologically differentiated from sporadic BCCs, and management largely depends on the size, location, recurrence, and number of lesions. Treatment methods range from topical agents to Mohs micrographic surgery.¹

Nonhealing lesions of the foot may give an initial clinical impression of infection overlying peripheral vascular disease or diabetes mellitus with the possibility of associated osteomyelitis. Our patient had no clinical history to suggest peripheral vascular disease or diabetes mellitus, and he had palpable dorsalis pedis pulses as well as a normal neurologic examination. Clinicians also may consider fungal infection in the differential diagnosis. Erosio interdigitalis blastomycetica is a superficial yeast infection described as a well-defined, red, shiny plaque found in chronically wet areas, usually affecting the third or fourth interdigital spaces of the fingers.⁷ However, the lack of improvement with antibiotics and antifungals argued against bacterial or fungal infection in our patient. Although BCC also is a common feature of Bazex Dupré-Christol syndrome, it also is characterized by follicular atrophoderma, milia, hypohidrosis, and hypotrichosis,⁸ which were not evident in our patient. Pseudomonas hot foot syndrome is characterized by painful, plantar, erythematous nodules after exposure to ontaminated water that typically is self-limited but does respond to antibiotics for Pseudomonas.⁹

Our patient underwent Mohs micrographic surgery with a complex repair utilizing a full-thickness skin graft. There were no signs of recurrence at 3-month follow-up, and he was counseled on the importance of sun-protective behaviors along with regular dermatologic follow-up.

The Diagnosis: Basal Cell Nevus Syndrome

Given the patient’s history of numerous basal cell carcinomas (BCCs), odontogenic keratocysts, palmar pits, and a nonhealing ulcer, the clinical presentation was highly suggestive of interdigital BCC in the setting of basal cell nevus syndrome (BCNS). A shave biopsy was performed revealing islands of basaloid cells with peripheral palisading and a retraction artifact surrounded by fibromyxoid stroma, consistent with nodular and infiltrative BCC (Figure 1).

Basal cell nevus syndrome (also known as Gorlin syndrome) is a rare neurocutaneous syndrome that manifests with multiple BCCs; palmar and plantar pits (Figure 2); central nervous system tumors; and skeletal anomalies including jaw cysts, macrocephaly, frontal bossing, and bifid ribs.¹ It is an autosomal-dominant condition caused by mutations in the PTCH1 gene, a tumor suppressor gene involved in the Hedgehog signaling pathway.² Basal cell carcinoma is the most distinctive feature of BCNS, causing notable morbidity. Tumors typically present between puberty and 35 years of age, and patients can have anywhere from a few to thousands of tumors. They rarely become locally aggressive; however, with radiation therapy, proliferation and local invasion may occur within a few years. Therefore, radiotherapy should be avoided in these patients.¹

Although the most common sites for BCCs in BCNS are the head, neck, and back, there is a higher rate of occurrence on sun-protected areas in BCNS compared to the general population.³ Our patient presented with interdigital BCC of the foot, which is an extremely rare occurrence. PubMed and Ovid searches using the terms basal cell carcinoma, BCC, foot, interdigital, and nonmelanoma skin cancer revealed only 3 cases of interdigital BCC of the foot. One case was associated with prior surgical trauma, the second presented as a junctional nevus, and the third did not appear to have any associated inciting factors.^4-6 Dermatologists need to have a low threshold for biopsy for any unusual nonhealing lesions, especially in the setting of BCNS. Basal cell carcinomas in BCNS cannot be histologically differentiated from sporadic BCCs, and management largely depends on the size, location, recurrence, and number of lesions. Treatment methods range from topical agents to Mohs micrographic surgery.¹

Nonhealing lesions of the foot may give an initial clinical impression of infection overlying peripheral vascular disease or diabetes mellitus with the possibility of associated osteomyelitis. Our patient had no clinical history to suggest peripheral vascular disease or diabetes mellitus, and he had palpable dorsalis pedis pulses as well as a normal neurologic examination. Clinicians also may consider fungal infection in the differential diagnosis. Erosio interdigitalis blastomycetica is a superficial yeast infection described as a well-defined, red, shiny plaque found in chronically wet areas, usually affecting the third or fourth interdigital spaces of the fingers.⁷ However, the lack of improvement with antibiotics and antifungals argued against bacterial or fungal infection in our patient. Although BCC also is a common feature of Bazex Dupré-Christol syndrome, it also is characterized by follicular atrophoderma, milia, hypohidrosis, and hypotrichosis,⁸ which were not evident in our patient. Pseudomonas hot foot syndrome is characterized by painful, plantar, erythematous nodules after exposure to ontaminated water that typically is self-limited but does respond to antibiotics for Pseudomonas.⁹

Our patient underwent Mohs micrographic surgery with a complex repair utilizing a full-thickness skin graft. There were no signs of recurrence at 3-month follow-up, and he was counseled on the importance of sun-protective behaviors along with regular dermatologic follow-up.

The Diagnosis: Basal Cell Nevus Syndrome

Given the patient’s history of numerous basal cell carcinomas (BCCs), odontogenic keratocysts, palmar pits, and a nonhealing ulcer, the clinical presentation was highly suggestive of interdigital BCC in the setting of basal cell nevus syndrome (BCNS). A shave biopsy was performed revealing islands of basaloid cells with peripheral palisading and a retraction artifact surrounded by fibromyxoid stroma, consistent with nodular and infiltrative BCC (Figure 1).

Basal cell nevus syndrome (also known as Gorlin syndrome) is a rare neurocutaneous syndrome that manifests with multiple BCCs; palmar and plantar pits (Figure 2); central nervous system tumors; and skeletal anomalies including jaw cysts, macrocephaly, frontal bossing, and bifid ribs.¹ It is an autosomal-dominant condition caused by mutations in the PTCH1 gene, a tumor suppressor gene involved in the Hedgehog signaling pathway.² Basal cell carcinoma is the most distinctive feature of BCNS, causing notable morbidity. Tumors typically present between puberty and 35 years of age, and patients can have anywhere from a few to thousands of tumors. They rarely become locally aggressive; however, with radiation therapy, proliferation and local invasion may occur within a few years. Therefore, radiotherapy should be avoided in these patients.¹

Although the most common sites for BCCs in BCNS are the head, neck, and back, there is a higher rate of occurrence on sun-protected areas in BCNS compared to the general population.³ Our patient presented with interdigital BCC of the foot, which is an extremely rare occurrence. PubMed and Ovid searches using the terms basal cell carcinoma, BCC, foot, interdigital, and nonmelanoma skin cancer revealed only 3 cases of interdigital BCC of the foot. One case was associated with prior surgical trauma, the second presented as a junctional nevus, and the third did not appear to have any associated inciting factors.^4-6 Dermatologists need to have a low threshold for biopsy for any unusual nonhealing lesions, especially in the setting of BCNS. Basal cell carcinomas in BCNS cannot be histologically differentiated from sporadic BCCs, and management largely depends on the size, location, recurrence, and number of lesions. Treatment methods range from topical agents to Mohs micrographic surgery.¹

Nonhealing lesions of the foot may give an initial clinical impression of infection overlying peripheral vascular disease or diabetes mellitus with the possibility of associated osteomyelitis. Our patient had no clinical history to suggest peripheral vascular disease or diabetes mellitus, and he had palpable dorsalis pedis pulses as well as a normal neurologic examination. Clinicians also may consider fungal infection in the differential diagnosis. Erosio interdigitalis blastomycetica is a superficial yeast infection described as a well-defined, red, shiny plaque found in chronically wet areas, usually affecting the third or fourth interdigital spaces of the fingers.⁷ However, the lack of improvement with antibiotics and antifungals argued against bacterial or fungal infection in our patient. Although BCC also is a common feature of Bazex Dupré-Christol syndrome, it also is characterized by follicular atrophoderma, milia, hypohidrosis, and hypotrichosis,⁸ which were not evident in our patient. Pseudomonas hot foot syndrome is characterized by painful, plantar, erythematous nodules after exposure to ontaminated water that typically is self-limited but does respond to antibiotics for Pseudomonas.⁹

Our patient underwent Mohs micrographic surgery with a complex repair utilizing a full-thickness skin graft. There were no signs of recurrence at 3-month follow-up, and he was counseled on the importance of sun-protective behaviors along with regular dermatologic follow-up.

The Diagnosis: Primary Cutaneous Nocardiosis

Comprehensive metabolic panel and complete blood cell count were unremarkable; human immunodeficiency virus screening was nonreactive. Punch biopsies were obtained for histopathology, as well as bacterial, fungal, and mycobacterial cultures. Histopathologic examination of a 4-mm punch biopsy of the forearm nodule showed a dermal abscess with neutrophilic infiltration in the dermis (Figure 1). No organisms were seen on Gram, methenamine-silver, periodic acid–Schiff, or acid-fast bacteria stains. Given the clinical suspicion for lymphocutaneous sporotrichosis, the patient was started on itraconazole. She reported modest improvement but subsequently developed a morbilliform eruption necessitating medication discontinuation.

Eighteen days after obtaining the tissue culture, acid-fast organisms grew in culture. These organisms were subcultured on Middlebrook 7H11 agar (Sigma-Aldrich) with growth noted at 30°C and 37°C. Gram stain revealed filamentous gram-variable bacteria (Figure 2) that were identified as Nocardia brasiliensis by 16S ribosomal DNA analysis. Given the patient’s sulfonamide allergy, she started oral minocycline 100 mg twice daily. She responded to the therapy and subsequent testing confirmed susceptibility.

The genus Nocardia consists of more than 50 species of gram-positive, weakly acid-fast, aerobic actinomycetes that can cause primary cutaneous infection via percutaneous inoculation. Nocardia brasiliensis is the leading cause (approximately 80% of cases) of primary cutaneous or subcutaneous nocardiosis and is found ubiquitously in soil and decaying vegetation.¹ The clinical presentation varies, rendering definitive diagnosis a challenge without histopathologic and microbiologic testing.² Patients presenting with nocardial cellulitis often are suspected to have Streptococcus pyogenes or Staphylococcus aureus infections. The differential diagnosis for patients presenting with nocardial nodular lymphangitis, also known as lymphocutaneous syndrome, includes atypical mycobacterial infections, leishmaniasis, and lymphocutaneous sporotrichosis.²

Histologic examination of nocardial nodules typically shows granulomatous or neutrophilic inflammation, and organisms may appear in small collections resembling sulfur granules.² The organism itself is weakly positive on acid-fast stain, and useful stains include acid-fast bacteria, methenamine silver, and periodic acid–Schiff.² Tissue culture often provides the definitive diagnosis, as the histology is nonspecific and organisms may not be visualized.

Oral trimethoprim-sulfamethoxazole 2.5 to 10 mg/kg and 12.5 to 50 mg/kg, respectively, twice daily is the treatment of choice for primary cutaneous nocardiosis. Minocycline 100 to 200 mg twice daily is an accepted alternative in case of sulfonamide allergy, as in our patient. Antibiotics should be tailored according to the susceptibility profile of the isolated organism.³

This case highlights the importance of forming a broad differential diagnosis for patients presenting with lymphocutaneous syndrome. The incidence and prevalence of N brasiliensis infection is difficult to determine due to its nonspecific clinical presentation and a lack of recent epidemiologic studies. Although primary cutaneous nocardiosis in the United States often is diagnosed in the South or Southwest, cases have been reported in other regions.^4-6 Traumatic inoculation of contaminated soil, plants, and other organic matter, a well-known method of Sporothrix schenckii transmission, also is a method of N brasiliensis transmission. Because this organism may not be detected on histologic examination, empiric treatment should be considered if the diagnosis is suspected.

The Diagnosis: Primary Cutaneous Nocardiosis

Comprehensive metabolic panel and complete blood cell count were unremarkable; human immunodeficiency virus screening was nonreactive. Punch biopsies were obtained for histopathology, as well as bacterial, fungal, and mycobacterial cultures. Histopathologic examination of a 4-mm punch biopsy of the forearm nodule showed a dermal abscess with neutrophilic infiltration in the dermis (Figure 1). No organisms were seen on Gram, methenamine-silver, periodic acid–Schiff, or acid-fast bacteria stains. Given the clinical suspicion for lymphocutaneous sporotrichosis, the patient was started on itraconazole. She reported modest improvement but subsequently developed a morbilliform eruption necessitating medication discontinuation.

Eighteen days after obtaining the tissue culture, acid-fast organisms grew in culture. These organisms were subcultured on Middlebrook 7H11 agar (Sigma-Aldrich) with growth noted at 30°C and 37°C. Gram stain revealed filamentous gram-variable bacteria (Figure 2) that were identified as Nocardia brasiliensis by 16S ribosomal DNA analysis. Given the patient’s sulfonamide allergy, she started oral minocycline 100 mg twice daily. She responded to the therapy and subsequent testing confirmed susceptibility.

The genus Nocardia consists of more than 50 species of gram-positive, weakly acid-fast, aerobic actinomycetes that can cause primary cutaneous infection via percutaneous inoculation. Nocardia brasiliensis is the leading cause (approximately 80% of cases) of primary cutaneous or subcutaneous nocardiosis and is found ubiquitously in soil and decaying vegetation.¹ The clinical presentation varies, rendering definitive diagnosis a challenge without histopathologic and microbiologic testing.² Patients presenting with nocardial cellulitis often are suspected to have Streptococcus pyogenes or Staphylococcus aureus infections. The differential diagnosis for patients presenting with nocardial nodular lymphangitis, also known as lymphocutaneous syndrome, includes atypical mycobacterial infections, leishmaniasis, and lymphocutaneous sporotrichosis.²

Histologic examination of nocardial nodules typically shows granulomatous or neutrophilic inflammation, and organisms may appear in small collections resembling sulfur granules.² The organism itself is weakly positive on acid-fast stain, and useful stains include acid-fast bacteria, methenamine silver, and periodic acid–Schiff.² Tissue culture often provides the definitive diagnosis, as the histology is nonspecific and organisms may not be visualized.

Oral trimethoprim-sulfamethoxazole 2.5 to 10 mg/kg and 12.5 to 50 mg/kg, respectively, twice daily is the treatment of choice for primary cutaneous nocardiosis. Minocycline 100 to 200 mg twice daily is an accepted alternative in case of sulfonamide allergy, as in our patient. Antibiotics should be tailored according to the susceptibility profile of the isolated organism.³

This case highlights the importance of forming a broad differential diagnosis for patients presenting with lymphocutaneous syndrome. The incidence and prevalence of N brasiliensis infection is difficult to determine due to its nonspecific clinical presentation and a lack of recent epidemiologic studies. Although primary cutaneous nocardiosis in the United States often is diagnosed in the South or Southwest, cases have been reported in other regions.^4-6 Traumatic inoculation of contaminated soil, plants, and other organic matter, a well-known method of Sporothrix schenckii transmission, also is a method of N brasiliensis transmission. Because this organism may not be detected on histologic examination, empiric treatment should be considered if the diagnosis is suspected.

The Diagnosis: Primary Cutaneous Nocardiosis

Comprehensive metabolic panel and complete blood cell count were unremarkable; human immunodeficiency virus screening was nonreactive. Punch biopsies were obtained for histopathology, as well as bacterial, fungal, and mycobacterial cultures. Histopathologic examination of a 4-mm punch biopsy of the forearm nodule showed a dermal abscess with neutrophilic infiltration in the dermis (Figure 1). No organisms were seen on Gram, methenamine-silver, periodic acid–Schiff, or acid-fast bacteria stains. Given the clinical suspicion for lymphocutaneous sporotrichosis, the patient was started on itraconazole. She reported modest improvement but subsequently developed a morbilliform eruption necessitating medication discontinuation.

Eighteen days after obtaining the tissue culture, acid-fast organisms grew in culture. These organisms were subcultured on Middlebrook 7H11 agar (Sigma-Aldrich) with growth noted at 30°C and 37°C. Gram stain revealed filamentous gram-variable bacteria (Figure 2) that were identified as Nocardia brasiliensis by 16S ribosomal DNA analysis. Given the patient’s sulfonamide allergy, she started oral minocycline 100 mg twice daily. She responded to the therapy and subsequent testing confirmed susceptibility.

The genus Nocardia consists of more than 50 species of gram-positive, weakly acid-fast, aerobic actinomycetes that can cause primary cutaneous infection via percutaneous inoculation. Nocardia brasiliensis is the leading cause (approximately 80% of cases) of primary cutaneous or subcutaneous nocardiosis and is found ubiquitously in soil and decaying vegetation.¹ The clinical presentation varies, rendering definitive diagnosis a challenge without histopathologic and microbiologic testing.² Patients presenting with nocardial cellulitis often are suspected to have Streptococcus pyogenes or Staphylococcus aureus infections. The differential diagnosis for patients presenting with nocardial nodular lymphangitis, also known as lymphocutaneous syndrome, includes atypical mycobacterial infections, leishmaniasis, and lymphocutaneous sporotrichosis.²

Histologic examination of nocardial nodules typically shows granulomatous or neutrophilic inflammation, and organisms may appear in small collections resembling sulfur granules.² The organism itself is weakly positive on acid-fast stain, and useful stains include acid-fast bacteria, methenamine silver, and periodic acid–Schiff.² Tissue culture often provides the definitive diagnosis, as the histology is nonspecific and organisms may not be visualized.

Oral trimethoprim-sulfamethoxazole 2.5 to 10 mg/kg and 12.5 to 50 mg/kg, respectively, twice daily is the treatment of choice for primary cutaneous nocardiosis. Minocycline 100 to 200 mg twice daily is an accepted alternative in case of sulfonamide allergy, as in our patient. Antibiotics should be tailored according to the susceptibility profile of the isolated organism.³

This case highlights the importance of forming a broad differential diagnosis for patients presenting with lymphocutaneous syndrome. The incidence and prevalence of N brasiliensis infection is difficult to determine due to its nonspecific clinical presentation and a lack of recent epidemiologic studies. Although primary cutaneous nocardiosis in the United States often is diagnosed in the South or Southwest, cases have been reported in other regions.^4-6 Traumatic inoculation of contaminated soil, plants, and other organic matter, a well-known method of Sporothrix schenckii transmission, also is a method of N brasiliensis transmission. Because this organism may not be detected on histologic examination, empiric treatment should be considered if the diagnosis is suspected.

Pityriasis amiantacea (PA) is characterized by adherence of hair shafts proximally.¹ It has been associated with dermatologic conditions and rarely with medications. We describe a woman who developed PA following a bone marrow transplant with melphalan conditioning. We also review drug-induced PA and disorders that have been linked to this condition.

Case Report

A 67-year-old woman with a history of multiple myeloma was treated with 7 courses of chemotherapy (cyclophosphamide, bortezomib, prednisone). One month later, the patient underwent a bone marrow transplant with melphalan conditioning due to residual plasma cell myeloma. Following the transplant, she developed complete scalp alopecia. Prior to and following transplant, the patient’s hair care regimen included washing her hair and scalp every other day with over-the-counter “natural” shampoos. During drug-induced alopecia, the hair washing became less frequent.

The patient left the hospital 4 weeks posttransplant; her hair had started to regrow, but its appearance was altered. Posttransplant, the patient was maintained on bortezomib every other week and zoledronate once per month. She continued to develop multiple lesions in the scalp hairs during the following 4 months.

Eight months posttransplant she presented for evaluation of the scalp hair. Clinical examination showed hairs that were entwined together proximally, resulting in matting of the hair (Figure 1). A diagnosis of PA was established based on the clinical examination.

Treatment included mineral oil application to the scalp under occlusion each evening, followed by morning washing with coal tar 0.5%, salicylic acid 6%, or ketoconazole 2% shampoo in a repeating sequential manner. Within 1 month there was complete resolution of the scalp condition (Figure 2).

Comment

Clinical Presentation                                                                                                                                                                                                                                                                                                                                                             
Pityriasis amiantacea is characterized by thick excessive scale of the scalp¹; it was initially described by Alibert² in 1832. He described the gross appearance of the scales as resembling the feathers of young birds, which naturalists dub “amiante” or asbestoslike.^1,2 In 1917, Gougerot³ explored infectious etiologies of this condition by describing cases of impetigo that transitioned into PA.¹ Later, in 1929, Photinos⁴ described fungal origins of PA, giving credence to “tinea amiantacea.”¹ However, more recent analyses failed to isolate fungus.^5-7 As such, pityriasis (scaling) amiantacea is the more appropriate term, as emphasized by Brown⁸ in 1948. The cause of PA remains unclear; it is hypothesized that the condition is a reaction to underlying inflammatory dermatoses, though concurrent bacterial or fungal infection may be present.^5,9

Prevalence                                                                                                                                                                                                                                                                                                                                                                             
Pityriasis amiantacea is considered to be most prevalent in pediatric patients and young adults; it is more common in females.^1,9,10 In a review of 85 PA patients, more than 80% were women (n=69), and the mean age at presentation was 23.8 years. Approximately half of these patients had widespread scalp lesions (n=42); however, focal localized lesions were common.⁹ No hereditary patterns have been described, though 3 pairs of the 10 patients with PA in Ring and Kaplan’s⁷ review were siblings.

Histopathology                                                                                                                                                                                                                                                                                                                                                                 
Submission of hair specimens to histopathology usually is not performed since the diagnosis often is established based on the clinical presentation.⁵ However, submitted specimens have demonstrated spongiosis and parakeratosis along with reduction in the size of the sebaceous glands.^1,9 Additionally, follicular keratosis that surrounds the hair shafts with a sheath of horn is present.⁹ Acanthosis and migration of lymphocytes into the epidermis also have been found.¹ Often, Staphylococcus aureus isolates are detected.^9,13
 

Differential Diagnosis                                                                                                                                                                                                                                                                                                                                                                   
The clinical differential diagnosis of PA includes hair casts,¹¹ pediculosis,¹⁴ and tinea capitis.¹² In PA, thick scales surround hair shafts and thus bind down tufts of hair.⁹ In patients with pediculosis, nits are attached to the hair shaft at an angle and do not entirely envelop the hair shaft.¹⁴ In addition, PA may be complicated by impetiginization; bacteria often are found in the keratin surrounding the hair shaft and represent either normal flora or secondary infection.^1,15 It has been speculated that microbial biofilms from S aureus and Staphylococcus epidermidis promote agglomeration of hair shafts and adherent scale.¹⁶ Bona fide dermatophyte infection of the scalp also may be concurrently present.¹²

Treatment                                                                                                                                                                                                                                                                                                                                                                                     
Our treatment included occlusion with mineral oil to loosen the scales from the scalp in tandem with shampoos traditionally used in patients with seborrheic dermatitis or psoriasis. Timely treatment is important to prevent scarring alopecia.^13,17 Pityriasis amiantacea may be treatment resistant, and there are no specific therapeutic guidelines; rather, therapy should be targeted at the suspected underlying condition.¹⁷ Treatment generally includes keratolytic agents, such as salicylic acid.¹⁸ These agents allow enhanced penetration of other topical agents.¹⁹ Topical antifungal shampoos such as ketoconazole and ciclopirox are recommended,¹⁸ though other topical agents, such as coal tar and zinc pyrithione, also may benefit patients.¹³ Topical corticosteroids may be used if the condition is linked with psoriasis.¹³ Systemic antibiotics are added if S aureus superinfection is suspected.⁹

A single report described successful management of a patient with severe refractory PA who was treated with the tumor necrosis factor (TNF) α inhibitor infliximab.¹³ A 47-year-old woman presented with thick adherent scale on the scalp. She was treated with coal tar for 18 months but showed no improvement; the patient was subsequently prescribed salicylic acid 10%, clobetasol solution, and coal tar shampoo. After 3 months, when no improvement was observed, the patient was offered infliximab but declined. For 6 years the patient was treated with salicylic acid 20%, clobetasol (foam, lotion, shampoo, and solution), and coal tar shampoo without improvement. She then consented to infliximab therapy; after 3 infusions at weeks 0, 2, and 6, she demonstrated notable improvement. The patient was maintained on infliximab every 8 weeks.¹³

Pathogenesis                                                                                                                                                                                                                                                                                                                                                                                 
The pathogenesis of PA has yet to be definitively established, and the condition is usually idiopathic. In addition to bacterial or fungal etiologies,^3,4 PA has been linked to medications (Table 1)^16,20,21 and systemic conditions (Table 2).^{1,3,5,7-10,12,22-25}

A PubMed search of articles indexed for MEDLINE using the search terms amiantacea, bone, drug, hair marrow, malignancy, melphalan, pityriasis, tinea, and transplant yielded 4 patients—2 men and 2 women (including our patient)—with possible drug-induced PA (Table 1)^16,20,21; however, the onset after 2 years of medication (TNF-α inhibitors) or resolution while still receiving the agent (vemurafenib) makes the drug-induced linkage weak. The patients ranged in age from 21 to 67 years, with the median age being 37.5 years. Medications included melphalan, TNF-α inhibitors (adalimumab, infliximab),^16,21 and vemurafenib²⁰; it is interesting that infliximab was the medication associated with eliciting PA in 1 patient yet was an effective therapy in another patient with treatment-resistant PA. The onset of PA occurred between 1 month (melphalan) and 24 months (TNF-α inhibitors) after drug initiation. The patients’ associated diseases included Crohn disease,^16,21 metastatic melanoma,²⁰ and multiple myeloma.

Other conditions have been described in patients with PA (Table 2). Indeed, PA may be a manifestation of an underlying inflammatory skin disease.⁹ In addition to dermatologic conditions, procedures or malignancy may be associated with the disease, as demonstrated in our patient. Most commonly, PA is seen in association with psoriasis and seborrheic dermatitis; atopic dermatitis, bacterial infection, fungal infection, lichen planus, and neurodermatitis also have been associated with PA.^{1,3,5,7-10,12,18,22-25}

Conclusion

Pityriasis amiantacea is a benign condition affecting the scalp hair. Albeit uncommon, it may appear in patients treated with medications such as melphalan, TNF-α inhibitors, and vemurafenib. In addition, it has been described in individuals with dermatologic conditions, systemic procedures, or underlying malignancy. Our patient developed PA following a bone marrow transplant after receiving conditioning with melphalan.

Pityriasis amiantacea (PA) is characterized by adherence of hair shafts proximally.¹ It has been associated with dermatologic conditions and rarely with medications. We describe a woman who developed PA following a bone marrow transplant with melphalan conditioning. We also review drug-induced PA and disorders that have been linked to this condition.

Case Report

A 67-year-old woman with a history of multiple myeloma was treated with 7 courses of chemotherapy (cyclophosphamide, bortezomib, prednisone). One month later, the patient underwent a bone marrow transplant with melphalan conditioning due to residual plasma cell myeloma. Following the transplant, she developed complete scalp alopecia. Prior to and following transplant, the patient’s hair care regimen included washing her hair and scalp every other day with over-the-counter “natural” shampoos. During drug-induced alopecia, the hair washing became less frequent.

The patient left the hospital 4 weeks posttransplant; her hair had started to regrow, but its appearance was altered. Posttransplant, the patient was maintained on bortezomib every other week and zoledronate once per month. She continued to develop multiple lesions in the scalp hairs during the following 4 months.

Eight months posttransplant she presented for evaluation of the scalp hair. Clinical examination showed hairs that were entwined together proximally, resulting in matting of the hair (Figure 1). A diagnosis of PA was established based on the clinical examination.

Treatment included mineral oil application to the scalp under occlusion each evening, followed by morning washing with coal tar 0.5%, salicylic acid 6%, or ketoconazole 2% shampoo in a repeating sequential manner. Within 1 month there was complete resolution of the scalp condition (Figure 2).

Comment

Clinical Presentation                                                                                                                                                                                                                                                                                                                                                             
Pityriasis amiantacea is characterized by thick excessive scale of the scalp¹; it was initially described by Alibert² in 1832. He described the gross appearance of the scales as resembling the feathers of young birds, which naturalists dub “amiante” or asbestoslike.^1,2 In 1917, Gougerot³ explored infectious etiologies of this condition by describing cases of impetigo that transitioned into PA.¹ Later, in 1929, Photinos⁴ described fungal origins of PA, giving credence to “tinea amiantacea.”¹ However, more recent analyses failed to isolate fungus.^5-7 As such, pityriasis (scaling) amiantacea is the more appropriate term, as emphasized by Brown⁸ in 1948. The cause of PA remains unclear; it is hypothesized that the condition is a reaction to underlying inflammatory dermatoses, though concurrent bacterial or fungal infection may be present.^5,9

Prevalence                                                                                                                                                                                                                                                                                                                                                                             
Pityriasis amiantacea is considered to be most prevalent in pediatric patients and young adults; it is more common in females.^1,9,10 In a review of 85 PA patients, more than 80% were women (n=69), and the mean age at presentation was 23.8 years. Approximately half of these patients had widespread scalp lesions (n=42); however, focal localized lesions were common.⁹ No hereditary patterns have been described, though 3 pairs of the 10 patients with PA in Ring and Kaplan’s⁷ review were siblings.

Histopathology                                                                                                                                                                                                                                                                                                                                                                 
Submission of hair specimens to histopathology usually is not performed since the diagnosis often is established based on the clinical presentation.⁵ However, submitted specimens have demonstrated spongiosis and parakeratosis along with reduction in the size of the sebaceous glands.^1,9 Additionally, follicular keratosis that surrounds the hair shafts with a sheath of horn is present.⁹ Acanthosis and migration of lymphocytes into the epidermis also have been found.¹ Often, Staphylococcus aureus isolates are detected.^9,13
 

Differential Diagnosis                                                                                                                                                                                                                                                                                                                                                                   
The clinical differential diagnosis of PA includes hair casts,¹¹ pediculosis,¹⁴ and tinea capitis.¹² In PA, thick scales surround hair shafts and thus bind down tufts of hair.⁹ In patients with pediculosis, nits are attached to the hair shaft at an angle and do not entirely envelop the hair shaft.¹⁴ In addition, PA may be complicated by impetiginization; bacteria often are found in the keratin surrounding the hair shaft and represent either normal flora or secondary infection.^1,15 It has been speculated that microbial biofilms from S aureus and Staphylococcus epidermidis promote agglomeration of hair shafts and adherent scale.¹⁶ Bona fide dermatophyte infection of the scalp also may be concurrently present.¹²

Treatment                                                                                                                                                                                                                                                                                                                                                                                     
Our treatment included occlusion with mineral oil to loosen the scales from the scalp in tandem with shampoos traditionally used in patients with seborrheic dermatitis or psoriasis. Timely treatment is important to prevent scarring alopecia.^13,17 Pityriasis amiantacea may be treatment resistant, and there are no specific therapeutic guidelines; rather, therapy should be targeted at the suspected underlying condition.¹⁷ Treatment generally includes keratolytic agents, such as salicylic acid.¹⁸ These agents allow enhanced penetration of other topical agents.¹⁹ Topical antifungal shampoos such as ketoconazole and ciclopirox are recommended,¹⁸ though other topical agents, such as coal tar and zinc pyrithione, also may benefit patients.¹³ Topical corticosteroids may be used if the condition is linked with psoriasis.¹³ Systemic antibiotics are added if S aureus superinfection is suspected.⁹

A single report described successful management of a patient with severe refractory PA who was treated with the tumor necrosis factor (TNF) α inhibitor infliximab.¹³ A 47-year-old woman presented with thick adherent scale on the scalp. She was treated with coal tar for 18 months but showed no improvement; the patient was subsequently prescribed salicylic acid 10%, clobetasol solution, and coal tar shampoo. After 3 months, when no improvement was observed, the patient was offered infliximab but declined. For 6 years the patient was treated with salicylic acid 20%, clobetasol (foam, lotion, shampoo, and solution), and coal tar shampoo without improvement. She then consented to infliximab therapy; after 3 infusions at weeks 0, 2, and 6, she demonstrated notable improvement. The patient was maintained on infliximab every 8 weeks.¹³

Pathogenesis                                                                                                                                                                                                                                                                                                                                                                                 
The pathogenesis of PA has yet to be definitively established, and the condition is usually idiopathic. In addition to bacterial or fungal etiologies,^3,4 PA has been linked to medications (Table 1)^16,20,21 and systemic conditions (Table 2).^{1,3,5,7-10,12,22-25}

A PubMed search of articles indexed for MEDLINE using the search terms amiantacea, bone, drug, hair marrow, malignancy, melphalan, pityriasis, tinea, and transplant yielded 4 patients—2 men and 2 women (including our patient)—with possible drug-induced PA (Table 1)^16,20,21; however, the onset after 2 years of medication (TNF-α inhibitors) or resolution while still receiving the agent (vemurafenib) makes the drug-induced linkage weak. The patients ranged in age from 21 to 67 years, with the median age being 37.5 years. Medications included melphalan, TNF-α inhibitors (adalimumab, infliximab),^16,21 and vemurafenib²⁰; it is interesting that infliximab was the medication associated with eliciting PA in 1 patient yet was an effective therapy in another patient with treatment-resistant PA. The onset of PA occurred between 1 month (melphalan) and 24 months (TNF-α inhibitors) after drug initiation. The patients’ associated diseases included Crohn disease,^16,21 metastatic melanoma,²⁰ and multiple myeloma.

Other conditions have been described in patients with PA (Table 2). Indeed, PA may be a manifestation of an underlying inflammatory skin disease.⁹ In addition to dermatologic conditions, procedures or malignancy may be associated with the disease, as demonstrated in our patient. Most commonly, PA is seen in association with psoriasis and seborrheic dermatitis; atopic dermatitis, bacterial infection, fungal infection, lichen planus, and neurodermatitis also have been associated with PA.^{1,3,5,7-10,12,18,22-25}

Conclusion

Pityriasis amiantacea is a benign condition affecting the scalp hair. Albeit uncommon, it may appear in patients treated with medications such as melphalan, TNF-α inhibitors, and vemurafenib. In addition, it has been described in individuals with dermatologic conditions, systemic procedures, or underlying malignancy. Our patient developed PA following a bone marrow transplant after receiving conditioning with melphalan.

Pityriasis amiantacea (PA) is characterized by adherence of hair shafts proximally.¹ It has been associated with dermatologic conditions and rarely with medications. We describe a woman who developed PA following a bone marrow transplant with melphalan conditioning. We also review drug-induced PA and disorders that have been linked to this condition.

Case Report

A 67-year-old woman with a history of multiple myeloma was treated with 7 courses of chemotherapy (cyclophosphamide, bortezomib, prednisone). One month later, the patient underwent a bone marrow transplant with melphalan conditioning due to residual plasma cell myeloma. Following the transplant, she developed complete scalp alopecia. Prior to and following transplant, the patient’s hair care regimen included washing her hair and scalp every other day with over-the-counter “natural” shampoos. During drug-induced alopecia, the hair washing became less frequent.

The patient left the hospital 4 weeks posttransplant; her hair had started to regrow, but its appearance was altered. Posttransplant, the patient was maintained on bortezomib every other week and zoledronate once per month. She continued to develop multiple lesions in the scalp hairs during the following 4 months.

Eight months posttransplant she presented for evaluation of the scalp hair. Clinical examination showed hairs that were entwined together proximally, resulting in matting of the hair (Figure 1). A diagnosis of PA was established based on the clinical examination.

Treatment included mineral oil application to the scalp under occlusion each evening, followed by morning washing with coal tar 0.5%, salicylic acid 6%, or ketoconazole 2% shampoo in a repeating sequential manner. Within 1 month there was complete resolution of the scalp condition (Figure 2).

Comment

Clinical Presentation                                                                                                                                                                                                                                                                                                                                                             
Pityriasis amiantacea is characterized by thick excessive scale of the scalp¹; it was initially described by Alibert² in 1832. He described the gross appearance of the scales as resembling the feathers of young birds, which naturalists dub “amiante” or asbestoslike.^1,2 In 1917, Gougerot³ explored infectious etiologies of this condition by describing cases of impetigo that transitioned into PA.¹ Later, in 1929, Photinos⁴ described fungal origins of PA, giving credence to “tinea amiantacea.”¹ However, more recent analyses failed to isolate fungus.^5-7 As such, pityriasis (scaling) amiantacea is the more appropriate term, as emphasized by Brown⁸ in 1948. The cause of PA remains unclear; it is hypothesized that the condition is a reaction to underlying inflammatory dermatoses, though concurrent bacterial or fungal infection may be present.^5,9

Prevalence                                                                                                                                                                                                                                                                                                                                                                             
Pityriasis amiantacea is considered to be most prevalent in pediatric patients and young adults; it is more common in females.^1,9,10 In a review of 85 PA patients, more than 80% were women (n=69), and the mean age at presentation was 23.8 years. Approximately half of these patients had widespread scalp lesions (n=42); however, focal localized lesions were common.⁹ No hereditary patterns have been described, though 3 pairs of the 10 patients with PA in Ring and Kaplan’s⁷ review were siblings.

Histopathology                                                                                                                                                                                                                                                                                                                                                                 
Submission of hair specimens to histopathology usually is not performed since the diagnosis often is established based on the clinical presentation.⁵ However, submitted specimens have demonstrated spongiosis and parakeratosis along with reduction in the size of the sebaceous glands.^1,9 Additionally, follicular keratosis that surrounds the hair shafts with a sheath of horn is present.⁹ Acanthosis and migration of lymphocytes into the epidermis also have been found.¹ Often, Staphylococcus aureus isolates are detected.^9,13
 

Differential Diagnosis                                                                                                                                                                                                                                                                                                                                                                   
The clinical differential diagnosis of PA includes hair casts,¹¹ pediculosis,¹⁴ and tinea capitis.¹² In PA, thick scales surround hair shafts and thus bind down tufts of hair.⁹ In patients with pediculosis, nits are attached to the hair shaft at an angle and do not entirely envelop the hair shaft.¹⁴ In addition, PA may be complicated by impetiginization; bacteria often are found in the keratin surrounding the hair shaft and represent either normal flora or secondary infection.^1,15 It has been speculated that microbial biofilms from S aureus and Staphylococcus epidermidis promote agglomeration of hair shafts and adherent scale.¹⁶ Bona fide dermatophyte infection of the scalp also may be concurrently present.¹²

Treatment                                                                                                                                                                                                                                                                                                                                                                                     
Our treatment included occlusion with mineral oil to loosen the scales from the scalp in tandem with shampoos traditionally used in patients with seborrheic dermatitis or psoriasis. Timely treatment is important to prevent scarring alopecia.^13,17 Pityriasis amiantacea may be treatment resistant, and there are no specific therapeutic guidelines; rather, therapy should be targeted at the suspected underlying condition.¹⁷ Treatment generally includes keratolytic agents, such as salicylic acid.¹⁸ These agents allow enhanced penetration of other topical agents.¹⁹ Topical antifungal shampoos such as ketoconazole and ciclopirox are recommended,¹⁸ though other topical agents, such as coal tar and zinc pyrithione, also may benefit patients.¹³ Topical corticosteroids may be used if the condition is linked with psoriasis.¹³ Systemic antibiotics are added if S aureus superinfection is suspected.⁹

A single report described successful management of a patient with severe refractory PA who was treated with the tumor necrosis factor (TNF) α inhibitor infliximab.¹³ A 47-year-old woman presented with thick adherent scale on the scalp. She was treated with coal tar for 18 months but showed no improvement; the patient was subsequently prescribed salicylic acid 10%, clobetasol solution, and coal tar shampoo. After 3 months, when no improvement was observed, the patient was offered infliximab but declined. For 6 years the patient was treated with salicylic acid 20%, clobetasol (foam, lotion, shampoo, and solution), and coal tar shampoo without improvement. She then consented to infliximab therapy; after 3 infusions at weeks 0, 2, and 6, she demonstrated notable improvement. The patient was maintained on infliximab every 8 weeks.¹³

Pathogenesis                                                                                                                                                                                                                                                                                                                                                                                 
The pathogenesis of PA has yet to be definitively established, and the condition is usually idiopathic. In addition to bacterial or fungal etiologies,^3,4 PA has been linked to medications (Table 1)^16,20,21 and systemic conditions (Table 2).^{1,3,5,7-10,12,22-25}

A PubMed search of articles indexed for MEDLINE using the search terms amiantacea, bone, drug, hair marrow, malignancy, melphalan, pityriasis, tinea, and transplant yielded 4 patients—2 men and 2 women (including our patient)—with possible drug-induced PA (Table 1)^16,20,21; however, the onset after 2 years of medication (TNF-α inhibitors) or resolution while still receiving the agent (vemurafenib) makes the drug-induced linkage weak. The patients ranged in age from 21 to 67 years, with the median age being 37.5 years. Medications included melphalan, TNF-α inhibitors (adalimumab, infliximab),^16,21 and vemurafenib²⁰; it is interesting that infliximab was the medication associated with eliciting PA in 1 patient yet was an effective therapy in another patient with treatment-resistant PA. The onset of PA occurred between 1 month (melphalan) and 24 months (TNF-α inhibitors) after drug initiation. The patients’ associated diseases included Crohn disease,^16,21 metastatic melanoma,²⁰ and multiple myeloma.

Other conditions have been described in patients with PA (Table 2). Indeed, PA may be a manifestation of an underlying inflammatory skin disease.⁹ In addition to dermatologic conditions, procedures or malignancy may be associated with the disease, as demonstrated in our patient. Most commonly, PA is seen in association with psoriasis and seborrheic dermatitis; atopic dermatitis, bacterial infection, fungal infection, lichen planus, and neurodermatitis also have been associated with PA.^{1,3,5,7-10,12,18,22-25}

Conclusion

Pityriasis amiantacea is a benign condition affecting the scalp hair. Albeit uncommon, it may appear in patients treated with medications such as melphalan, TNF-α inhibitors, and vemurafenib. In addition, it has been described in individuals with dermatologic conditions, systemic procedures, or underlying malignancy. Our patient developed PA following a bone marrow transplant after receiving conditioning with melphalan.