Cutis

The Diagnosis: Calcinosis Cutis Due to Systemic Sclerosis Sine Scleroderma

Laboratory evaluation was notable for high titers of antinuclear antibodies (>1/320; reference range, 0–1/80) and positive anticentromere antibodies. There were no other relevant laboratory findings; phosphocalcic metabolism was within normal limits, and urinary sediment was normal. Biopsy of the edge of the ulcer revealed basophilic material compatible with calcium deposits. In a 3D volume rendering reconstruction from the lower limb scanner, grouped calcifications were observed in subcutaneous cellular tissue near the ulcer (Figure). The patient had a restrictive ventilatory pattern observed in a pulmonary function test. An esophageal motility study was normal.

The patient was diagnosed with systemic sclerosis sine scleroderma (ssSSc) type II because she met the 4 criteria established by Poormoghim et al¹ : (1) Raynaud phenomenon or a peripheral vascular equivalent (ie, digital pitting scars, digital-tip ulcers, digital-tip gangrene, abnormal nail fold capillaries); (2) positive antinuclear antibodies; (3) distal esophageal hypomotility, small bowel hypomotility, pulmonary interstitial fibrosis, primary pulmonary arterial hypertension (without fibrosis), cardiac involvement typical of scleroderma, or renal failure; and (4) no other defined connective tissue or other disease as a cause of the prior conditions.

Systemic sclerosis is a chronic disease characterized by progressive fibrosis of the skin and other internal organs—especially the lungs, kidneys, digestive tract, and heart—as well as generalized vascular dysfunction. Cutaneous induration is its hallmark; however, up to 10% of affected patients have ssSSc.² This entity is characterized by the total or partial absence of cutaneous manifestations of systemic sclerosis with the occurrence of internal organ involvement and serologic abnormalities. There are 3 types of ssSSc depending on the grade of skin involvement. Type I is characterized by the lack of any typical cutaneous stigmata of the disease. Type II is without sclerodactyly but can coexist with other cutaneous findings such as calcifications, telangiectases, or pitting scars. Type III is characterized clinically by internal organ involvement, typical of systemic sclerosis, that has appeared before skin changes.²

An abnormal deposit of calcium in the cutaneous and subcutaneous tissue is called calcinosis cutis. There are 5 subtypes of calcinosis cutis: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Dystrophic skin calcifications may appear in patients with connective tissue diseases such as dermatomyositis or systemic sclerosis.³ Up to 25% of patients with systemic sclerosis can develop calcinosis cutis due to local tissue damage, with normal phosphocalcic metabolism.³

Calcinosis cutis is more common in patients with systemic sclerosis and positive anticentromere antibodies.⁴ The calcifications usually are located in areas that are subject to repeated trauma, such as the fingers or arms, though other locations have been described such as cervical, paraspinal, or on the hips.^5,6 Our patient developed calcifications on both legs, which represent atypical areas for this process.

Dermatomyositis also can present with calcinosis cutis. There are 4 patterns of calcification: superficial nodulelike calcified masses; deep calcified masses; deep sheetlike calcifications within the fascial planes; and a rare, diffuse, superficial lacy and reticular calcification that involves almost the entire body surface area.⁷ Patients with calcinosis cutis secondary to dermatomyositis usually develop proximal muscle weakness, high titers of creatine kinase, heliotrope rash, or interstitial lung disease with specific antibodies.

Calciphylaxis is a serious disorder involving the calcification of dermal and subcutaneous arterioles and capillaries. It presents with painful cutaneous areas of necrosis.

Venous ulcers also can present with secondary dystrophic calcification due to local tissue damage. These patients usually have cutaneous signs of chronic venous insufficiency. Our patient denied prior trauma to the area; therefore, a traumatic ulcer with secondary calcification was ruled out.

The most concerning complication of calcinosis cutis is the development of ulcers, which occurred in 154 of 316 calcinoses (48.7%) in patients with systemic sclerosis and secondary calcifications.⁸ These ulcers can cause disabling pain or become superinfected, as in our patient.

There currently is no drug capable of removing dystrophic calcifications, but diltiazem, minocycline, or colchicine can reduce their size and prevent their progression. In the event of neurologic compromise or intractable pain, the treatment of choice is surgical removal of the calcification.⁹ Curettage, intralesional sodium thiosulfate, and intravenous sodium thiosulfate also have been suggested as therapeutic options.¹⁰ Antibiotic treatment was carried out in our patient, which controlled the superinfection of the ulcers. Diltiazem also was started, with stabilization of the calcium deposits without a reduction in their size.

There are few studies evaluating the presence of nondigital ulcers in patients with systemic sclerosis. Shanmugam et al¹¹ calculated a 4% (N=249) prevalence of ulcers in the lower limbs of systemic sclerosis patients. In a study by Bohelay et al¹² of 45 patients, the estimated prevalence of lower limb ulcers was 12.8%, and the etiologies consisted of 22 cases of venous insufficiency (49%), 21 cases of ischemic causes (47%), and 2 cases of other causes (4%).

We present the case of a woman with ssSSc who developed dystrophic calcinosis cutis in atypical areas with secondary ulceration and superinfection. The skin usually plays a key role in the diagnosis of systemic sclerosis, as sclerodactyly and the characteristic generalized skin induration stand out in affected individuals. Although our patient was diagnosed with ssSSc, her skin manifestations also were crucial for the diagnosis, as she had ulcers on the lower limbs.

The Diagnosis: Calcinosis Cutis Due to Systemic Sclerosis Sine Scleroderma

Laboratory evaluation was notable for high titers of antinuclear antibodies (>1/320; reference range, 0–1/80) and positive anticentromere antibodies. There were no other relevant laboratory findings; phosphocalcic metabolism was within normal limits, and urinary sediment was normal. Biopsy of the edge of the ulcer revealed basophilic material compatible with calcium deposits. In a 3D volume rendering reconstruction from the lower limb scanner, grouped calcifications were observed in subcutaneous cellular tissue near the ulcer (Figure). The patient had a restrictive ventilatory pattern observed in a pulmonary function test. An esophageal motility study was normal.

The patient was diagnosed with systemic sclerosis sine scleroderma (ssSSc) type II because she met the 4 criteria established by Poormoghim et al¹ : (1) Raynaud phenomenon or a peripheral vascular equivalent (ie, digital pitting scars, digital-tip ulcers, digital-tip gangrene, abnormal nail fold capillaries); (2) positive antinuclear antibodies; (3) distal esophageal hypomotility, small bowel hypomotility, pulmonary interstitial fibrosis, primary pulmonary arterial hypertension (without fibrosis), cardiac involvement typical of scleroderma, or renal failure; and (4) no other defined connective tissue or other disease as a cause of the prior conditions.

Systemic sclerosis is a chronic disease characterized by progressive fibrosis of the skin and other internal organs—especially the lungs, kidneys, digestive tract, and heart—as well as generalized vascular dysfunction. Cutaneous induration is its hallmark; however, up to 10% of affected patients have ssSSc.² This entity is characterized by the total or partial absence of cutaneous manifestations of systemic sclerosis with the occurrence of internal organ involvement and serologic abnormalities. There are 3 types of ssSSc depending on the grade of skin involvement. Type I is characterized by the lack of any typical cutaneous stigmata of the disease. Type II is without sclerodactyly but can coexist with other cutaneous findings such as calcifications, telangiectases, or pitting scars. Type III is characterized clinically by internal organ involvement, typical of systemic sclerosis, that has appeared before skin changes.²

An abnormal deposit of calcium in the cutaneous and subcutaneous tissue is called calcinosis cutis. There are 5 subtypes of calcinosis cutis: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Dystrophic skin calcifications may appear in patients with connective tissue diseases such as dermatomyositis or systemic sclerosis.³ Up to 25% of patients with systemic sclerosis can develop calcinosis cutis due to local tissue damage, with normal phosphocalcic metabolism.³

Calcinosis cutis is more common in patients with systemic sclerosis and positive anticentromere antibodies.⁴ The calcifications usually are located in areas that are subject to repeated trauma, such as the fingers or arms, though other locations have been described such as cervical, paraspinal, or on the hips.^5,6 Our patient developed calcifications on both legs, which represent atypical areas for this process.

Dermatomyositis also can present with calcinosis cutis. There are 4 patterns of calcification: superficial nodulelike calcified masses; deep calcified masses; deep sheetlike calcifications within the fascial planes; and a rare, diffuse, superficial lacy and reticular calcification that involves almost the entire body surface area.⁷ Patients with calcinosis cutis secondary to dermatomyositis usually develop proximal muscle weakness, high titers of creatine kinase, heliotrope rash, or interstitial lung disease with specific antibodies.

Calciphylaxis is a serious disorder involving the calcification of dermal and subcutaneous arterioles and capillaries. It presents with painful cutaneous areas of necrosis.

Venous ulcers also can present with secondary dystrophic calcification due to local tissue damage. These patients usually have cutaneous signs of chronic venous insufficiency. Our patient denied prior trauma to the area; therefore, a traumatic ulcer with secondary calcification was ruled out.

The most concerning complication of calcinosis cutis is the development of ulcers, which occurred in 154 of 316 calcinoses (48.7%) in patients with systemic sclerosis and secondary calcifications.⁸ These ulcers can cause disabling pain or become superinfected, as in our patient.

There currently is no drug capable of removing dystrophic calcifications, but diltiazem, minocycline, or colchicine can reduce their size and prevent their progression. In the event of neurologic compromise or intractable pain, the treatment of choice is surgical removal of the calcification.⁹ Curettage, intralesional sodium thiosulfate, and intravenous sodium thiosulfate also have been suggested as therapeutic options.¹⁰ Antibiotic treatment was carried out in our patient, which controlled the superinfection of the ulcers. Diltiazem also was started, with stabilization of the calcium deposits without a reduction in their size.

There are few studies evaluating the presence of nondigital ulcers in patients with systemic sclerosis. Shanmugam et al¹¹ calculated a 4% (N=249) prevalence of ulcers in the lower limbs of systemic sclerosis patients. In a study by Bohelay et al¹² of 45 patients, the estimated prevalence of lower limb ulcers was 12.8%, and the etiologies consisted of 22 cases of venous insufficiency (49%), 21 cases of ischemic causes (47%), and 2 cases of other causes (4%).

We present the case of a woman with ssSSc who developed dystrophic calcinosis cutis in atypical areas with secondary ulceration and superinfection. The skin usually plays a key role in the diagnosis of systemic sclerosis, as sclerodactyly and the characteristic generalized skin induration stand out in affected individuals. Although our patient was diagnosed with ssSSc, her skin manifestations also were crucial for the diagnosis, as she had ulcers on the lower limbs.

The Diagnosis: Calcinosis Cutis Due to Systemic Sclerosis Sine Scleroderma

Laboratory evaluation was notable for high titers of antinuclear antibodies (>1/320; reference range, 0–1/80) and positive anticentromere antibodies. There were no other relevant laboratory findings; phosphocalcic metabolism was within normal limits, and urinary sediment was normal. Biopsy of the edge of the ulcer revealed basophilic material compatible with calcium deposits. In a 3D volume rendering reconstruction from the lower limb scanner, grouped calcifications were observed in subcutaneous cellular tissue near the ulcer (Figure). The patient had a restrictive ventilatory pattern observed in a pulmonary function test. An esophageal motility study was normal.

The patient was diagnosed with systemic sclerosis sine scleroderma (ssSSc) type II because she met the 4 criteria established by Poormoghim et al¹ : (1) Raynaud phenomenon or a peripheral vascular equivalent (ie, digital pitting scars, digital-tip ulcers, digital-tip gangrene, abnormal nail fold capillaries); (2) positive antinuclear antibodies; (3) distal esophageal hypomotility, small bowel hypomotility, pulmonary interstitial fibrosis, primary pulmonary arterial hypertension (without fibrosis), cardiac involvement typical of scleroderma, or renal failure; and (4) no other defined connective tissue or other disease as a cause of the prior conditions.

Systemic sclerosis is a chronic disease characterized by progressive fibrosis of the skin and other internal organs—especially the lungs, kidneys, digestive tract, and heart—as well as generalized vascular dysfunction. Cutaneous induration is its hallmark; however, up to 10% of affected patients have ssSSc.² This entity is characterized by the total or partial absence of cutaneous manifestations of systemic sclerosis with the occurrence of internal organ involvement and serologic abnormalities. There are 3 types of ssSSc depending on the grade of skin involvement. Type I is characterized by the lack of any typical cutaneous stigmata of the disease. Type II is without sclerodactyly but can coexist with other cutaneous findings such as calcifications, telangiectases, or pitting scars. Type III is characterized clinically by internal organ involvement, typical of systemic sclerosis, that has appeared before skin changes.²

An abnormal deposit of calcium in the cutaneous and subcutaneous tissue is called calcinosis cutis. There are 5 subtypes of calcinosis cutis: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Dystrophic skin calcifications may appear in patients with connective tissue diseases such as dermatomyositis or systemic sclerosis.³ Up to 25% of patients with systemic sclerosis can develop calcinosis cutis due to local tissue damage, with normal phosphocalcic metabolism.³

Calcinosis cutis is more common in patients with systemic sclerosis and positive anticentromere antibodies.⁴ The calcifications usually are located in areas that are subject to repeated trauma, such as the fingers or arms, though other locations have been described such as cervical, paraspinal, or on the hips.^5,6 Our patient developed calcifications on both legs, which represent atypical areas for this process.

Dermatomyositis also can present with calcinosis cutis. There are 4 patterns of calcification: superficial nodulelike calcified masses; deep calcified masses; deep sheetlike calcifications within the fascial planes; and a rare, diffuse, superficial lacy and reticular calcification that involves almost the entire body surface area.⁷ Patients with calcinosis cutis secondary to dermatomyositis usually develop proximal muscle weakness, high titers of creatine kinase, heliotrope rash, or interstitial lung disease with specific antibodies.

Calciphylaxis is a serious disorder involving the calcification of dermal and subcutaneous arterioles and capillaries. It presents with painful cutaneous areas of necrosis.

Venous ulcers also can present with secondary dystrophic calcification due to local tissue damage. These patients usually have cutaneous signs of chronic venous insufficiency. Our patient denied prior trauma to the area; therefore, a traumatic ulcer with secondary calcification was ruled out.

The most concerning complication of calcinosis cutis is the development of ulcers, which occurred in 154 of 316 calcinoses (48.7%) in patients with systemic sclerosis and secondary calcifications.⁸ These ulcers can cause disabling pain or become superinfected, as in our patient.

There currently is no drug capable of removing dystrophic calcifications, but diltiazem, minocycline, or colchicine can reduce their size and prevent their progression. In the event of neurologic compromise or intractable pain, the treatment of choice is surgical removal of the calcification.⁹ Curettage, intralesional sodium thiosulfate, and intravenous sodium thiosulfate also have been suggested as therapeutic options.¹⁰ Antibiotic treatment was carried out in our patient, which controlled the superinfection of the ulcers. Diltiazem also was started, with stabilization of the calcium deposits without a reduction in their size.

There are few studies evaluating the presence of nondigital ulcers in patients with systemic sclerosis. Shanmugam et al¹¹ calculated a 4% (N=249) prevalence of ulcers in the lower limbs of systemic sclerosis patients. In a study by Bohelay et al¹² of 45 patients, the estimated prevalence of lower limb ulcers was 12.8%, and the etiologies consisted of 22 cases of venous insufficiency (49%), 21 cases of ischemic causes (47%), and 2 cases of other causes (4%).

We present the case of a woman with ssSSc who developed dystrophic calcinosis cutis in atypical areas with secondary ulceration and superinfection. The skin usually plays a key role in the diagnosis of systemic sclerosis, as sclerodactyly and the characteristic generalized skin induration stand out in affected individuals. Although our patient was diagnosed with ssSSc, her skin manifestations also were crucial for the diagnosis, as she had ulcers on the lower limbs.

To the Editor:

Lymphangioma circumscriptum (LC) is a benign malformation of the lymphatic system.¹ It is postulated to arise from abnormal lymphatic cisterns, and it grows separately from the normal lymphatic system. These cisterns are connected to malformed dermal lymphatic channels, and the contraction of smooth muscles lining cisterns will cause dilatation of connected lymphatic channels in the papillary dermis due to back pressure,^1,2 which causes a classic LC manifestation characterized by multiple translucent, sometimes red-brown, small vesicles grouped together. Lymphangioma circumscriptum can be difficult to differentiate from molluscum contagiosum (MC) due to the similar morphology.¹ We present a notable case of MC superimposed on LC.

A 6-year-old girl presented with multiple grouped, clear, vesicular papules on the right buttock of 18 months’ duration. Some of the papules showed tiny whitish pearl-like particles on the top (Figure 1). Similar lesions were not present elsewhere on the body. She had no underlying disease and did not have a history of procedure, edema, or malformation of the lower extremities. Histopathology from one of the lesions showed dilated cystic lymphatic spaces in the papillary dermis lined with flattened endothelium and cup-shaped downward proliferation of the epidermis with presence of large intracytoplasmic inclusion bodies—features of both LC and MC (Figure 2). We waited 4 additional months for the MC lesions to self-resolve, but they persisted. The patient’s mother strongly requested for their removal, and the residual MC lesions were carefully removed by CO₂ laser. To prevent unnecessary physical damage to underlying LC lesions and minimize scarring, we opted to use the CO₂ laser and not simple curettage. She currently is under periodic observation with no signs of clinical recurrence of MC, but the LC lesions naturally persisted.

Due to its vesicular and sometimes warty appearance, LC can sometimes be hard to differentiate from MC. In one report, a vesicular plaquelike lesion on the trunk initially was misdiagnosed and treated as MC but was histologically confirmed as LC several years later.³ Our case demonstrates the coexistence of MC and LC. Although this phenomenon may be coincidental, we have not noticed any additional MC lesions on the body and MC only existed over the LC lesions, implying a possible pathophysiologic relationship. It is unlikely that MC might have preceded the development of LC. Although acquired LC exists, it has mostly been reported in the genital region of patients with conditions leading to lymphatic obstruction such as surgery, radiation therapy, malignancy, or serious infections.⁴ Because our patient developed lesions at an early age without any remarkable medical history, it is likely that she had congenital LC that was secondarily infected by the MC virus. Vesicular lesions in LC are known to rupture easily and may serve as a vulnerable entry site for pathogens. Subsequent secondary bacterial infections are common, with Staphylococcus aureus being the most prominent entity.¹ However, secondary viral infection rarely is reported. It is possible that the abnormally dilated lymphatic channels of LC that lack communication with the normal lymphatic system have contributed to an LC site-specific vulnerability to MC virus. Further studies and subsequent reports are required to confirm this hypothesis.

To the Editor:

Lymphangioma circumscriptum (LC) is a benign malformation of the lymphatic system.¹ It is postulated to arise from abnormal lymphatic cisterns, and it grows separately from the normal lymphatic system. These cisterns are connected to malformed dermal lymphatic channels, and the contraction of smooth muscles lining cisterns will cause dilatation of connected lymphatic channels in the papillary dermis due to back pressure,^1,2 which causes a classic LC manifestation characterized by multiple translucent, sometimes red-brown, small vesicles grouped together. Lymphangioma circumscriptum can be difficult to differentiate from molluscum contagiosum (MC) due to the similar morphology.¹ We present a notable case of MC superimposed on LC.

A 6-year-old girl presented with multiple grouped, clear, vesicular papules on the right buttock of 18 months’ duration. Some of the papules showed tiny whitish pearl-like particles on the top (Figure 1). Similar lesions were not present elsewhere on the body. She had no underlying disease and did not have a history of procedure, edema, or malformation of the lower extremities. Histopathology from one of the lesions showed dilated cystic lymphatic spaces in the papillary dermis lined with flattened endothelium and cup-shaped downward proliferation of the epidermis with presence of large intracytoplasmic inclusion bodies—features of both LC and MC (Figure 2). We waited 4 additional months for the MC lesions to self-resolve, but they persisted. The patient’s mother strongly requested for their removal, and the residual MC lesions were carefully removed by CO₂ laser. To prevent unnecessary physical damage to underlying LC lesions and minimize scarring, we opted to use the CO₂ laser and not simple curettage. She currently is under periodic observation with no signs of clinical recurrence of MC, but the LC lesions naturally persisted.

Due to its vesicular and sometimes warty appearance, LC can sometimes be hard to differentiate from MC. In one report, a vesicular plaquelike lesion on the trunk initially was misdiagnosed and treated as MC but was histologically confirmed as LC several years later.³ Our case demonstrates the coexistence of MC and LC. Although this phenomenon may be coincidental, we have not noticed any additional MC lesions on the body and MC only existed over the LC lesions, implying a possible pathophysiologic relationship. It is unlikely that MC might have preceded the development of LC. Although acquired LC exists, it has mostly been reported in the genital region of patients with conditions leading to lymphatic obstruction such as surgery, radiation therapy, malignancy, or serious infections.⁴ Because our patient developed lesions at an early age without any remarkable medical history, it is likely that she had congenital LC that was secondarily infected by the MC virus. Vesicular lesions in LC are known to rupture easily and may serve as a vulnerable entry site for pathogens. Subsequent secondary bacterial infections are common, with Staphylococcus aureus being the most prominent entity.¹ However, secondary viral infection rarely is reported. It is possible that the abnormally dilated lymphatic channels of LC that lack communication with the normal lymphatic system have contributed to an LC site-specific vulnerability to MC virus. Further studies and subsequent reports are required to confirm this hypothesis.

To the Editor:

Lymphangioma circumscriptum (LC) is a benign malformation of the lymphatic system.¹ It is postulated to arise from abnormal lymphatic cisterns, and it grows separately from the normal lymphatic system. These cisterns are connected to malformed dermal lymphatic channels, and the contraction of smooth muscles lining cisterns will cause dilatation of connected lymphatic channels in the papillary dermis due to back pressure,^1,2 which causes a classic LC manifestation characterized by multiple translucent, sometimes red-brown, small vesicles grouped together. Lymphangioma circumscriptum can be difficult to differentiate from molluscum contagiosum (MC) due to the similar morphology.¹ We present a notable case of MC superimposed on LC.

A 6-year-old girl presented with multiple grouped, clear, vesicular papules on the right buttock of 18 months’ duration. Some of the papules showed tiny whitish pearl-like particles on the top (Figure 1). Similar lesions were not present elsewhere on the body. She had no underlying disease and did not have a history of procedure, edema, or malformation of the lower extremities. Histopathology from one of the lesions showed dilated cystic lymphatic spaces in the papillary dermis lined with flattened endothelium and cup-shaped downward proliferation of the epidermis with presence of large intracytoplasmic inclusion bodies—features of both LC and MC (Figure 2). We waited 4 additional months for the MC lesions to self-resolve, but they persisted. The patient’s mother strongly requested for their removal, and the residual MC lesions were carefully removed by CO₂ laser. To prevent unnecessary physical damage to underlying LC lesions and minimize scarring, we opted to use the CO₂ laser and not simple curettage. She currently is under periodic observation with no signs of clinical recurrence of MC, but the LC lesions naturally persisted.

Due to its vesicular and sometimes warty appearance, LC can sometimes be hard to differentiate from MC. In one report, a vesicular plaquelike lesion on the trunk initially was misdiagnosed and treated as MC but was histologically confirmed as LC several years later.³ Our case demonstrates the coexistence of MC and LC. Although this phenomenon may be coincidental, we have not noticed any additional MC lesions on the body and MC only existed over the LC lesions, implying a possible pathophysiologic relationship. It is unlikely that MC might have preceded the development of LC. Although acquired LC exists, it has mostly been reported in the genital region of patients with conditions leading to lymphatic obstruction such as surgery, radiation therapy, malignancy, or serious infections.⁴ Because our patient developed lesions at an early age without any remarkable medical history, it is likely that she had congenital LC that was secondarily infected by the MC virus. Vesicular lesions in LC are known to rupture easily and may serve as a vulnerable entry site for pathogens. Subsequent secondary bacterial infections are common, with Staphylococcus aureus being the most prominent entity.¹ However, secondary viral infection rarely is reported. It is possible that the abnormally dilated lymphatic channels of LC that lack communication with the normal lymphatic system have contributed to an LC site-specific vulnerability to MC virus. Further studies and subsequent reports are required to confirm this hypothesis.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

The Diagnosis: Striated Muscle Hamartoma

Histopathologic evaluation revealed a dome-shaped papule with a center composed of mature striated muscle bundles, vellus hairs, sebaceous lobules, and nerve twigs (Figure) consistent with a diagnosis of striated muscle hamartoma (SMH).

Striated muscle hamartoma was first described in 1986 by Hendrick et al1 with 2 cases in neonates. Biopsies of the lesions taken from the upper lip and sternum showed a characteristic histology consisting of dermal striated muscle fibers and nerve bundles in the central core of the papules associated with a marked number of adnexa. In 1989, the diagnosis of rhabdomyomatous mesenchymal hamartoma was described, which showed similar findings.² Cases reported since these entities were discovered have used the terms striated muscle hamartoma and rhabdomyomatous mesenchymal hamartoma interchangeably.³

Most commonly found on the head and neck, SMH has now been observed in diverse locations including the sternum, hallux, vagina, and oral cavity.^1-15 Many reported cases describe lesions around or in the nose.^4,7,8 Multiple congenital anomalies have been described alongside SMH and may be associated with this entity including amniotic bands, cleft lip and palate, coloboma, and Delleman syndrome.^1,3,4 Almost all of the lesions present as a sessile or pedunculated papule, polyp, nodule, or plaque measuring from 0.3 cm up to 4.9 cm and typically are present since birth.^3,5,15 However, there are a few cases of lesions presenting in adults with no prior history.^5,6,15

Microscopically, SMH is defined by a dermal lesion with a core comprised of mature skeletal muscle admixed with adipose tissue, adnexa, nerve bundles, and fibrovascular tissue.¹ There are other entities that should be considered before making the diagnosis of SMH. Other hamartomas such as accessory tragus, connective tissue nevus, fibrous hamartoma of infancy, and nevus lipomatosis may present similarly; however, these lesions classically lack skeletal muscle. Benign triton tumors, or neuromuscular hamartomas, are rare lesions composed of skeletal muscle and abundant, intimately associated neural tissue. Neuromuscular hamartomas frequently involve large nerves.¹⁶ Rhabdomyomas also should be considered. Adult rhabdomyomas are composed of eosinophilic polygonal cells with granular cytoplasm and occasional cross-striations. Fetal rhabdomyomas have multiple histologic types and are defined by a variable myxoid stroma, eosinophilic spindled cells, and rhabdomyocytes in various stages of maturity. Genital rhabdomyomas histopathologically appear similar to fetal rhabdomyomas but are confined to the genital region. The skeletal muscle present in rhabdomyomas typically is less differentiated.¹⁷ TMature skeletal bundles should be a dominant component of the lesion before diagnosing SMH.

Typically presenting as congenital lesions in the head and neck region, papules with a dermal core of mature skeletal muscle associated with adnexa and nerve twigs should prompt consideration of a diagnosis of SMH or rhabdomyomatous mesenchymal hamartoma. These lesions are benign and usually are cured with complete excision.

The Diagnosis: Striated Muscle Hamartoma

Histopathologic evaluation revealed a dome-shaped papule with a center composed of mature striated muscle bundles, vellus hairs, sebaceous lobules, and nerve twigs (Figure) consistent with a diagnosis of striated muscle hamartoma (SMH).

Striated muscle hamartoma was first described in 1986 by Hendrick et al1 with 2 cases in neonates. Biopsies of the lesions taken from the upper lip and sternum showed a characteristic histology consisting of dermal striated muscle fibers and nerve bundles in the central core of the papules associated with a marked number of adnexa. In 1989, the diagnosis of rhabdomyomatous mesenchymal hamartoma was described, which showed similar findings.² Cases reported since these entities were discovered have used the terms striated muscle hamartoma and rhabdomyomatous mesenchymal hamartoma interchangeably.³

Most commonly found on the head and neck, SMH has now been observed in diverse locations including the sternum, hallux, vagina, and oral cavity.^1-15 Many reported cases describe lesions around or in the nose.^4,7,8 Multiple congenital anomalies have been described alongside SMH and may be associated with this entity including amniotic bands, cleft lip and palate, coloboma, and Delleman syndrome.^1,3,4 Almost all of the lesions present as a sessile or pedunculated papule, polyp, nodule, or plaque measuring from 0.3 cm up to 4.9 cm and typically are present since birth.^3,5,15 However, there are a few cases of lesions presenting in adults with no prior history.^5,6,15

Microscopically, SMH is defined by a dermal lesion with a core comprised of mature skeletal muscle admixed with adipose tissue, adnexa, nerve bundles, and fibrovascular tissue.¹ There are other entities that should be considered before making the diagnosis of SMH. Other hamartomas such as accessory tragus, connective tissue nevus, fibrous hamartoma of infancy, and nevus lipomatosis may present similarly; however, these lesions classically lack skeletal muscle. Benign triton tumors, or neuromuscular hamartomas, are rare lesions composed of skeletal muscle and abundant, intimately associated neural tissue. Neuromuscular hamartomas frequently involve large nerves.¹⁶ Rhabdomyomas also should be considered. Adult rhabdomyomas are composed of eosinophilic polygonal cells with granular cytoplasm and occasional cross-striations. Fetal rhabdomyomas have multiple histologic types and are defined by a variable myxoid stroma, eosinophilic spindled cells, and rhabdomyocytes in various stages of maturity. Genital rhabdomyomas histopathologically appear similar to fetal rhabdomyomas but are confined to the genital region. The skeletal muscle present in rhabdomyomas typically is less differentiated.¹⁷ TMature skeletal bundles should be a dominant component of the lesion before diagnosing SMH.

Typically presenting as congenital lesions in the head and neck region, papules with a dermal core of mature skeletal muscle associated with adnexa and nerve twigs should prompt consideration of a diagnosis of SMH or rhabdomyomatous mesenchymal hamartoma. These lesions are benign and usually are cured with complete excision.

The Diagnosis: Striated Muscle Hamartoma

Histopathologic evaluation revealed a dome-shaped papule with a center composed of mature striated muscle bundles, vellus hairs, sebaceous lobules, and nerve twigs (Figure) consistent with a diagnosis of striated muscle hamartoma (SMH).

Striated muscle hamartoma was first described in 1986 by Hendrick et al1 with 2 cases in neonates. Biopsies of the lesions taken from the upper lip and sternum showed a characteristic histology consisting of dermal striated muscle fibers and nerve bundles in the central core of the papules associated with a marked number of adnexa. In 1989, the diagnosis of rhabdomyomatous mesenchymal hamartoma was described, which showed similar findings.² Cases reported since these entities were discovered have used the terms striated muscle hamartoma and rhabdomyomatous mesenchymal hamartoma interchangeably.³

Most commonly found on the head and neck, SMH has now been observed in diverse locations including the sternum, hallux, vagina, and oral cavity.^1-15 Many reported cases describe lesions around or in the nose.^4,7,8 Multiple congenital anomalies have been described alongside SMH and may be associated with this entity including amniotic bands, cleft lip and palate, coloboma, and Delleman syndrome.^1,3,4 Almost all of the lesions present as a sessile or pedunculated papule, polyp, nodule, or plaque measuring from 0.3 cm up to 4.9 cm and typically are present since birth.^3,5,15 However, there are a few cases of lesions presenting in adults with no prior history.^5,6,15

Microscopically, SMH is defined by a dermal lesion with a core comprised of mature skeletal muscle admixed with adipose tissue, adnexa, nerve bundles, and fibrovascular tissue.¹ There are other entities that should be considered before making the diagnosis of SMH. Other hamartomas such as accessory tragus, connective tissue nevus, fibrous hamartoma of infancy, and nevus lipomatosis may present similarly; however, these lesions classically lack skeletal muscle. Benign triton tumors, or neuromuscular hamartomas, are rare lesions composed of skeletal muscle and abundant, intimately associated neural tissue. Neuromuscular hamartomas frequently involve large nerves.¹⁶ Rhabdomyomas also should be considered. Adult rhabdomyomas are composed of eosinophilic polygonal cells with granular cytoplasm and occasional cross-striations. Fetal rhabdomyomas have multiple histologic types and are defined by a variable myxoid stroma, eosinophilic spindled cells, and rhabdomyocytes in various stages of maturity. Genital rhabdomyomas histopathologically appear similar to fetal rhabdomyomas but are confined to the genital region. The skeletal muscle present in rhabdomyomas typically is less differentiated.¹⁷ TMature skeletal bundles should be a dominant component of the lesion before diagnosing SMH.

Typically presenting as congenital lesions in the head and neck region, papules with a dermal core of mature skeletal muscle associated with adnexa and nerve twigs should prompt consideration of a diagnosis of SMH or rhabdomyomatous mesenchymal hamartoma. These lesions are benign and usually are cured with complete excision.

The Diagnosis: Ecthyma Gangrenosum

Histopathology revealed basophilic bacterial rods around necrotic vessels with thrombosis and edema (Figure). Blood and tissue cultures grew Pseudomonas aeruginosa. Based on the histopathology and clinical presentation, a diagnosis of P aeruginosa–associated ecthyma gangrenosum (EG) was made. The patient’s symptoms resolved with intravenous cefepime, and he later was transitioned to oral levofloxacin for outpatient treatment.

Ecthyma gangrenosum is an uncommon cutaneous manifestation of bacteremia that most commonly occurs secondary to P aeruginosa in immunocompromised patients, particularly patients with severe neutropenia in the setting of recent chemotherapy.^1,2 Ecthyma gangrenosum can occur anywhere on the body, predominantly in moist areas such as the axillae and groin; the arms and legs, such as in our patient, as well as the trunk and face also may be involved.³ Other causes of EG skin lesions include methicillin-resistant Staphylococcus aureus, Citrobacter freundii, Escherichia coli, fungi such as Candida, and viruses such as herpes simplex virus.^2,4-6 Common predisposing conditions associated with EG include neutropenia, leukemia, HIV, diabetes mellitus, extensive burn wounds, and a history of immunosuppressive medications. It also has been known to occur in otherwise healthy, immunocompetent individuals with no difference in clinical manifestation.²

The diagnosis is clinicopathologic, with initial evaluation including blood and wound cultures as well as a complete blood cell count once EG is suspected. An excisional or punch biopsy is performed for confirmation, showing many gram-negative, rod-shaped bacteria in cases of pseudomonal EG.⁷ Histopathology is characterized by bacterial perivascular invasion that then leads to secondary arteriole thrombosis, tissue edema, and separation of the epidermis.^7,8 Resultant ischemic necrosis results in the classic macroscopic appearance of an erythematous macule that rapidly progresses into a central necrotic lesion surrounded by an erythematous or violaceous halo after undergoing a hemorrhagic bullous stage.1,9 A Wood lamp can be used to expedite the diagnosis, as Pseudomonas bacteria excretes a pigment (pyoverdine) that fluoresces yellowish green.¹⁰

Ecthyma gangrenosum can be classified as a primary skin lesion that may or may not be followed by bacteremia or as a lesion secondary to pseudomonal bacteremia.¹¹ Bacteremia has been reported in half of cases, with hematogenous metastasis of the infection, likely in manifestations with multiple bilateral lesions.² Our patient’s presentation of a single lesion revealed a positive blood culture result. Lesions also can develop by direct inoculation of the epidermis causing local destruction of the surrounding tissue. The nonbacteremic form of EG has been associated with a lower mortality rate of around 15% compared to patients with bacteremia ranging from 38% to 96%.¹² The presence of neutropenia is the most important prognostic factor for mortality at the time of diagnosis.¹³

Prompt empiric therapy should be initiated after obtaining wound and blood cultures in those with infection until the causative organism and its susceptibility are identified. Pseudomonal infections account for 4% of all cases of hospital-acquired bacteremia and are the third leading cause of gram-negative bloodstream infection.⁷ Initial broad-spectrum antibiotics include antipseudomonal β-lactams (piperacillin-tazobactam), cephalosporins (cefepime), fluoroquinolones (levofloxacin), and carbapenems (imipenem).^1,7 Medical therapy alone may be sufficient without requiring extensive surgical debridement to remove necrotic tissue in some patients. Surgical debridement usually is warranted for lesions larger than 10 cm in diameter.³ Our patient was treated with intravenous cefepime with resolution and was followed with outpatient oral levofloxacin as appropriate. A high index of suspicion should be maintained for relapsing pseudomonal EG infection among patients with AIDS, as the reported recurrence rate is 57%.¹⁴

Clinically, the differential diagnosis of EG presenting in immunocompromised patients or individuals with underlying malignancy includes pyoderma gangrenosum, papulonecrotic tuberculid, and leukemia cutis. An erythematous rash with central necrosis presenting in a patient with systemic symptoms is pathognomonic for erythema migrans and should be considered as a diagnostic possibility in areas endemic for Lyme disease in the United States, including the northeastern, mid-Atlantic, and north-central regions.¹⁵ A thorough history, physical examination, basic laboratory studies, and histopathology are critical to differentiate between these entities with similar macroscopic features. Pyoderma gangrenosum histologically manifests as a noninfectious, deep, suppurative folliculitis with leukocytoclastic vasculitis in 40% of cases.¹⁶ Although papulonecrotic tuberculid can present with dermal necrosis resulting from a hypersensitivity reaction to antigenic components of mycobacteria, there typically are granulomatous infiltrates present and a lack of observed organisms on histopathology.¹⁷ Although leukemia cutis infrequently occurs in patients diagnosed with leukemia, its salient features on pathology are nodular or diffuse infiltrates of leukemic cells in the dermis and subcutis with a high nuclear-to-cytoplasmic ratio, often with prominent nucleoli.¹⁸ Lyme disease can present in various ways; however, cutaneous involvement in the primary lesion is histologically characterized by a perivascular lymphohistiocytic infiltrate containing plasma cells at the periphery of the expanding annular lesion and eosinophils present at the center.¹⁹

The Diagnosis: Ecthyma Gangrenosum

Histopathology revealed basophilic bacterial rods around necrotic vessels with thrombosis and edema (Figure). Blood and tissue cultures grew Pseudomonas aeruginosa. Based on the histopathology and clinical presentation, a diagnosis of P aeruginosa–associated ecthyma gangrenosum (EG) was made. The patient’s symptoms resolved with intravenous cefepime, and he later was transitioned to oral levofloxacin for outpatient treatment.

Ecthyma gangrenosum is an uncommon cutaneous manifestation of bacteremia that most commonly occurs secondary to P aeruginosa in immunocompromised patients, particularly patients with severe neutropenia in the setting of recent chemotherapy.^1,2 Ecthyma gangrenosum can occur anywhere on the body, predominantly in moist areas such as the axillae and groin; the arms and legs, such as in our patient, as well as the trunk and face also may be involved.³ Other causes of EG skin lesions include methicillin-resistant Staphylococcus aureus, Citrobacter freundii, Escherichia coli, fungi such as Candida, and viruses such as herpes simplex virus.^2,4-6 Common predisposing conditions associated with EG include neutropenia, leukemia, HIV, diabetes mellitus, extensive burn wounds, and a history of immunosuppressive medications. It also has been known to occur in otherwise healthy, immunocompetent individuals with no difference in clinical manifestation.²

The diagnosis is clinicopathologic, with initial evaluation including blood and wound cultures as well as a complete blood cell count once EG is suspected. An excisional or punch biopsy is performed for confirmation, showing many gram-negative, rod-shaped bacteria in cases of pseudomonal EG.⁷ Histopathology is characterized by bacterial perivascular invasion that then leads to secondary arteriole thrombosis, tissue edema, and separation of the epidermis.^7,8 Resultant ischemic necrosis results in the classic macroscopic appearance of an erythematous macule that rapidly progresses into a central necrotic lesion surrounded by an erythematous or violaceous halo after undergoing a hemorrhagic bullous stage.1,9 A Wood lamp can be used to expedite the diagnosis, as Pseudomonas bacteria excretes a pigment (pyoverdine) that fluoresces yellowish green.¹⁰

Ecthyma gangrenosum can be classified as a primary skin lesion that may or may not be followed by bacteremia or as a lesion secondary to pseudomonal bacteremia.¹¹ Bacteremia has been reported in half of cases, with hematogenous metastasis of the infection, likely in manifestations with multiple bilateral lesions.² Our patient’s presentation of a single lesion revealed a positive blood culture result. Lesions also can develop by direct inoculation of the epidermis causing local destruction of the surrounding tissue. The nonbacteremic form of EG has been associated with a lower mortality rate of around 15% compared to patients with bacteremia ranging from 38% to 96%.¹² The presence of neutropenia is the most important prognostic factor for mortality at the time of diagnosis.¹³

Prompt empiric therapy should be initiated after obtaining wound and blood cultures in those with infection until the causative organism and its susceptibility are identified. Pseudomonal infections account for 4% of all cases of hospital-acquired bacteremia and are the third leading cause of gram-negative bloodstream infection.⁷ Initial broad-spectrum antibiotics include antipseudomonal β-lactams (piperacillin-tazobactam), cephalosporins (cefepime), fluoroquinolones (levofloxacin), and carbapenems (imipenem).^1,7 Medical therapy alone may be sufficient without requiring extensive surgical debridement to remove necrotic tissue in some patients. Surgical debridement usually is warranted for lesions larger than 10 cm in diameter.³ Our patient was treated with intravenous cefepime with resolution and was followed with outpatient oral levofloxacin as appropriate. A high index of suspicion should be maintained for relapsing pseudomonal EG infection among patients with AIDS, as the reported recurrence rate is 57%.¹⁴

Clinically, the differential diagnosis of EG presenting in immunocompromised patients or individuals with underlying malignancy includes pyoderma gangrenosum, papulonecrotic tuberculid, and leukemia cutis. An erythematous rash with central necrosis presenting in a patient with systemic symptoms is pathognomonic for erythema migrans and should be considered as a diagnostic possibility in areas endemic for Lyme disease in the United States, including the northeastern, mid-Atlantic, and north-central regions.¹⁵ A thorough history, physical examination, basic laboratory studies, and histopathology are critical to differentiate between these entities with similar macroscopic features. Pyoderma gangrenosum histologically manifests as a noninfectious, deep, suppurative folliculitis with leukocytoclastic vasculitis in 40% of cases.¹⁶ Although papulonecrotic tuberculid can present with dermal necrosis resulting from a hypersensitivity reaction to antigenic components of mycobacteria, there typically are granulomatous infiltrates present and a lack of observed organisms on histopathology.¹⁷ Although leukemia cutis infrequently occurs in patients diagnosed with leukemia, its salient features on pathology are nodular or diffuse infiltrates of leukemic cells in the dermis and subcutis with a high nuclear-to-cytoplasmic ratio, often with prominent nucleoli.¹⁸ Lyme disease can present in various ways; however, cutaneous involvement in the primary lesion is histologically characterized by a perivascular lymphohistiocytic infiltrate containing plasma cells at the periphery of the expanding annular lesion and eosinophils present at the center.¹⁹

The Diagnosis: Ecthyma Gangrenosum

Histopathology revealed basophilic bacterial rods around necrotic vessels with thrombosis and edema (Figure). Blood and tissue cultures grew Pseudomonas aeruginosa. Based on the histopathology and clinical presentation, a diagnosis of P aeruginosa–associated ecthyma gangrenosum (EG) was made. The patient’s symptoms resolved with intravenous cefepime, and he later was transitioned to oral levofloxacin for outpatient treatment.

Ecthyma gangrenosum is an uncommon cutaneous manifestation of bacteremia that most commonly occurs secondary to P aeruginosa in immunocompromised patients, particularly patients with severe neutropenia in the setting of recent chemotherapy.^1,2 Ecthyma gangrenosum can occur anywhere on the body, predominantly in moist areas such as the axillae and groin; the arms and legs, such as in our patient, as well as the trunk and face also may be involved.³ Other causes of EG skin lesions include methicillin-resistant Staphylococcus aureus, Citrobacter freundii, Escherichia coli, fungi such as Candida, and viruses such as herpes simplex virus.^2,4-6 Common predisposing conditions associated with EG include neutropenia, leukemia, HIV, diabetes mellitus, extensive burn wounds, and a history of immunosuppressive medications. It also has been known to occur in otherwise healthy, immunocompetent individuals with no difference in clinical manifestation.²

The diagnosis is clinicopathologic, with initial evaluation including blood and wound cultures as well as a complete blood cell count once EG is suspected. An excisional or punch biopsy is performed for confirmation, showing many gram-negative, rod-shaped bacteria in cases of pseudomonal EG.⁷ Histopathology is characterized by bacterial perivascular invasion that then leads to secondary arteriole thrombosis, tissue edema, and separation of the epidermis.^7,8 Resultant ischemic necrosis results in the classic macroscopic appearance of an erythematous macule that rapidly progresses into a central necrotic lesion surrounded by an erythematous or violaceous halo after undergoing a hemorrhagic bullous stage.1,9 A Wood lamp can be used to expedite the diagnosis, as Pseudomonas bacteria excretes a pigment (pyoverdine) that fluoresces yellowish green.¹⁰

Ecthyma gangrenosum can be classified as a primary skin lesion that may or may not be followed by bacteremia or as a lesion secondary to pseudomonal bacteremia.¹¹ Bacteremia has been reported in half of cases, with hematogenous metastasis of the infection, likely in manifestations with multiple bilateral lesions.² Our patient’s presentation of a single lesion revealed a positive blood culture result. Lesions also can develop by direct inoculation of the epidermis causing local destruction of the surrounding tissue. The nonbacteremic form of EG has been associated with a lower mortality rate of around 15% compared to patients with bacteremia ranging from 38% to 96%.¹² The presence of neutropenia is the most important prognostic factor for mortality at the time of diagnosis.¹³

Prompt empiric therapy should be initiated after obtaining wound and blood cultures in those with infection until the causative organism and its susceptibility are identified. Pseudomonal infections account for 4% of all cases of hospital-acquired bacteremia and are the third leading cause of gram-negative bloodstream infection.⁷ Initial broad-spectrum antibiotics include antipseudomonal β-lactams (piperacillin-tazobactam), cephalosporins (cefepime), fluoroquinolones (levofloxacin), and carbapenems (imipenem).^1,7 Medical therapy alone may be sufficient without requiring extensive surgical debridement to remove necrotic tissue in some patients. Surgical debridement usually is warranted for lesions larger than 10 cm in diameter.³ Our patient was treated with intravenous cefepime with resolution and was followed with outpatient oral levofloxacin as appropriate. A high index of suspicion should be maintained for relapsing pseudomonal EG infection among patients with AIDS, as the reported recurrence rate is 57%.¹⁴

Clinically, the differential diagnosis of EG presenting in immunocompromised patients or individuals with underlying malignancy includes pyoderma gangrenosum, papulonecrotic tuberculid, and leukemia cutis. An erythematous rash with central necrosis presenting in a patient with systemic symptoms is pathognomonic for erythema migrans and should be considered as a diagnostic possibility in areas endemic for Lyme disease in the United States, including the northeastern, mid-Atlantic, and north-central regions.¹⁵ A thorough history, physical examination, basic laboratory studies, and histopathology are critical to differentiate between these entities with similar macroscopic features. Pyoderma gangrenosum histologically manifests as a noninfectious, deep, suppurative folliculitis with leukocytoclastic vasculitis in 40% of cases.¹⁶ Although papulonecrotic tuberculid can present with dermal necrosis resulting from a hypersensitivity reaction to antigenic components of mycobacteria, there typically are granulomatous infiltrates present and a lack of observed organisms on histopathology.¹⁷ Although leukemia cutis infrequently occurs in patients diagnosed with leukemia, its salient features on pathology are nodular or diffuse infiltrates of leukemic cells in the dermis and subcutis with a high nuclear-to-cytoplasmic ratio, often with prominent nucleoli.¹⁸ Lyme disease can present in various ways; however, cutaneous involvement in the primary lesion is histologically characterized by a perivascular lymphohistiocytic infiltrate containing plasma cells at the periphery of the expanding annular lesion and eosinophils present at the center.¹⁹

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

Opzelura FDA Approved for Atopic Dermatitis Incyte

Corporation announces US Food and Drug Administration (FDA) approval of Opzelura (ruxolitinib) cream 1.5% for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis (AD) in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Opzelura is formulated with ruxolitinib, a selective Janus kinase (JAK) 1/JAK2 inhibitor, to target key cytokine signals believed to contribute to itch and inflammation. For more information, visit www.opzelurahcp.com/.

Twyneo FDA Approved for Acne Vulgaris

Sol-Gel Technologies, Ltd, announces US Food and Drug Administration (FDA) approval of Twyneo (tretinoin 0.1% /benzoyl peroxide 3%) cream for the treatment of acne vulgaris in adult and pediatric patients 9 years and older. Tretinoin and benzoyl peroxide are widely prescribed separately for acne vulgaris; however, benzoyl peroxide causes degradation of the tretinoin molecule, thereby potentially reducing its effectiveness if used at the same time or combined in the same formulation. The formulation of Twyneo uses silica (silicon dioxide) core shell structures to separately microencapsulate tretinoin crystals and benzoyl peroxide crystals, enabling inclusion of the 2 active ingredients in the cream. For more information, visit www.sol-gel.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@mdedge.com.

Opzelura FDA Approved for Atopic Dermatitis Incyte

Corporation announces US Food and Drug Administration (FDA) approval of Opzelura (ruxolitinib) cream 1.5% for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis (AD) in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Opzelura is formulated with ruxolitinib, a selective Janus kinase (JAK) 1/JAK2 inhibitor, to target key cytokine signals believed to contribute to itch and inflammation. For more information, visit www.opzelurahcp.com/.

Twyneo FDA Approved for Acne Vulgaris

Sol-Gel Technologies, Ltd, announces US Food and Drug Administration (FDA) approval of Twyneo (tretinoin 0.1% /benzoyl peroxide 3%) cream for the treatment of acne vulgaris in adult and pediatric patients 9 years and older. Tretinoin and benzoyl peroxide are widely prescribed separately for acne vulgaris; however, benzoyl peroxide causes degradation of the tretinoin molecule, thereby potentially reducing its effectiveness if used at the same time or combined in the same formulation. The formulation of Twyneo uses silica (silicon dioxide) core shell structures to separately microencapsulate tretinoin crystals and benzoyl peroxide crystals, enabling inclusion of the 2 active ingredients in the cream. For more information, visit www.sol-gel.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@mdedge.com.

Opzelura FDA Approved for Atopic Dermatitis Incyte

Corporation announces US Food and Drug Administration (FDA) approval of Opzelura (ruxolitinib) cream 1.5% for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis (AD) in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Opzelura is formulated with ruxolitinib, a selective Janus kinase (JAK) 1/JAK2 inhibitor, to target key cytokine signals believed to contribute to itch and inflammation. For more information, visit www.opzelurahcp.com/.

Twyneo FDA Approved for Acne Vulgaris

Sol-Gel Technologies, Ltd, announces US Food and Drug Administration (FDA) approval of Twyneo (tretinoin 0.1% /benzoyl peroxide 3%) cream for the treatment of acne vulgaris in adult and pediatric patients 9 years and older. Tretinoin and benzoyl peroxide are widely prescribed separately for acne vulgaris; however, benzoyl peroxide causes degradation of the tretinoin molecule, thereby potentially reducing its effectiveness if used at the same time or combined in the same formulation. The formulation of Twyneo uses silica (silicon dioxide) core shell structures to separately microencapsulate tretinoin crystals and benzoyl peroxide crystals, enabling inclusion of the 2 active ingredients in the cream. For more information, visit www.sol-gel.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@mdedge.com.

The COVID-19 pandemic has markedly changed the dermatology residency application process. As medical students head into this application cycle, the impacts of systemic racism and deeply rooted structural barriers continue to be exacerbated for students who identify as an underrepresented minority (URM) in medicine—historically defined as those who self-identify as Hispanic or Latinx; Black or African American; American Indian or Alaska Native; or Native Hawaiian or Pacific Islander. The Association of American Medical Colleges (AAMC) defines URMs as racial and ethnic populations that are underrepresented in medicine relative to their numbers in the general population.¹ Although these groups account for approximately 34% of the population of the United States, they constitute only 11% of the country’s physician workforce.^2,3

Of the total physician workforce in the United States, Black and African American physicians account for 5% of practicing physicians; Hispanic physicians, 5.8%; American Indian and Alaska Native physicians, 0.3%; and Native Hawaiian and Pacific Islander physicians, 0.1%.² In competitive medical specialties, the disproportionality of these numbers compared to our current demographics in the United States as shown above is even more staggering. In 2018, for example, 10% of practicing dermatologists identified as female URM physicians; 6%, as male URM physicians.² In this article, we discuss some of the challenges and considerations for URM students applying to dermatology residency in the era of the COVID-19 pandemic.

Barriers for URM Students in Dermatology

Multiple studies have attempted to identify some of the barriers faced by URM students in medicine that might explain the lack of diversity in competitive specialties. Vasquez and colleagues⁴ identified 4 major factors that play a role in dermatology: lack of equitable resources, lack of support, financial limitations, and the lack of group identity. More than half of URM students surveyed (1) identified lack of support as a barrier and (2) reported having been encouraged to seek a specialty more reflective of their community.⁴

Soliman et al⁵ reported that URM barriers in dermatology extend to include lack of diversity in the field, socioeconomic factors, lack of mentorship, and a negative perception of minority students by residency programs. Dermatology is the second least diverse specialty in medicine after orthopedic surgery, which, in and of itself, might further discourage URM students from applying to dermatology.⁵

With the minimal exposure that URM students have to the field of dermatology, the lack of pipeline programs, and reports that URMs often are encouraged to pursue primary care, the current diversity deficiency in dermatology comes as no surprise. In addition, the substantial disadvantage for URM students is perpetuated by the traditional highly selective process that favors grades, board scores, and honor society status over holistic assessment of the individual student and their unique experiences and potential for contribution.

Looking Beyond Test Scores

The US Medical Licensing Examination (USMLE) traditionally has been used to select dermatology residency applicants, with high cutoff scores often excluding outstanding URM students. Research has suggested that the use of USMLE examination test scores for residency recruitment lacks validity because it has poor predictability of residency performance.⁶ Although the USMLE Step 1 examination is transitioning to pass/fail scoring, applicants for the next cycle will still have a 3-digit numerical score.

We strongly recommend that dermatology programs transition from emphasizing scores of residency candidates to reviewing each candidate holistically. The AAMC defines “holistic review” as a “flexible, individualized way of assessing an applicant’s capabilities, by which balanced consideration is given to experiences, attributes, competencies, and academic or scholarly metrics and, when considered in combination, how the individual might contribute value to the institution’s mission.”⁷ Furthermore, we recommend that dermatology residency programs have multiple faculty members review each application, including a representative of the diversity, inclusion, and equity committee.

In the COVID-19 era, dermatology externship opportunities that would have allowed URM students to work directly with potential residency programs, showcase their abilities, and network have been limited. Virtual residency interviews could make it more challenging to evaluate candidates, especially URM students from less prestigious programs or unusual socioeconomic backgrounds, or with lower board scores. In addition, virtual interviews can more easily become one-dimensional, depriving URM students of the opportunity to gauge their personal fit in a specific dermatology residency program and its community. Questions and concerns of URM students might include: Will I be appropriately supported and mentored? Will my cultural preferences, religion, sexual preference, hairstyle, and beliefs be accepted? Can I advocate for minorities and support antiracism and diversity and inclusion initiatives? To that end, we recommend that dermatology programs continue to host virtual meet-and-greet events for potential students to meet faculty and learn more about the program. In addition, programs should consider having current residents interact virtually with candidates to allow students to better understand the culture of the department and residents’ experiences as trainees in such an environment. For URM students, this is highly important because diversity, inclusion, and antiracism policies and initiatives might not be explicitly available on the institution’s website or residency information page.

Organizations Championing Diversity

Recently, multiple dermatology societies and organizations have been emphasizing the need for diversity and inclusion as well as promoting holistic application review. The American Academy of Dermatology pioneered the Diversity Champion Workshop in 2019 and continues to offer the Diversity Mentorship program, connecting URM students to mentors nationally. The Skin of Color Society offers yearly grants and awards to medical students to develop mentorship and research, and recently hosted webinars to guide medical students and residency programs on diversity and inclusion, residency application and review, and COVID-19 virtual interviews. Other national societies, such as the Student National Medical Association and Latino Medical Student Association, have been promoting workshops and interview mentoring for URM students, including dermatology-specific events. Although it is estimated that more than 90% of medical schools in the United States already perform holistic application review and that such review has been adopted by many dermatology programs nationwide, data regarding dermatology residency programs’ implementation of holistic application review are lacking.⁸

In addition, we encourage continuation of the proposed coordinated interview invite release from the Association of Professors of Dermatology, which was implemented in the 2020-2021 cycle. In light of the recent AAMC letter⁹ on the maldistribution of interview invitations to highest-tier applicants, coordination of interview release dates and other similar initiatives to prevent programs from offering more invites than their available slots and improve transparency about interview days are needed. Furthermore, continuing to offer optional virtual interviews for applicants in future cycles could make the process less cost-prohibitive for many URM students.^4,5

Final Thoughts

Dermatology residency programs must intentionally guard against falling back to traditional standards of assessment as the only means of student evaluation, especially in this virtual era. It is our responsibility to remove artificial barriers that continue to stall progress in diversity, inclusion, equity, and belonging in dermatology.

The COVID-19 pandemic has markedly changed the dermatology residency application process. As medical students head into this application cycle, the impacts of systemic racism and deeply rooted structural barriers continue to be exacerbated for students who identify as an underrepresented minority (URM) in medicine—historically defined as those who self-identify as Hispanic or Latinx; Black or African American; American Indian or Alaska Native; or Native Hawaiian or Pacific Islander. The Association of American Medical Colleges (AAMC) defines URMs as racial and ethnic populations that are underrepresented in medicine relative to their numbers in the general population.¹ Although these groups account for approximately 34% of the population of the United States, they constitute only 11% of the country’s physician workforce.^2,3

Of the total physician workforce in the United States, Black and African American physicians account for 5% of practicing physicians; Hispanic physicians, 5.8%; American Indian and Alaska Native physicians, 0.3%; and Native Hawaiian and Pacific Islander physicians, 0.1%.² In competitive medical specialties, the disproportionality of these numbers compared to our current demographics in the United States as shown above is even more staggering. In 2018, for example, 10% of practicing dermatologists identified as female URM physicians; 6%, as male URM physicians.² In this article, we discuss some of the challenges and considerations for URM students applying to dermatology residency in the era of the COVID-19 pandemic.

Barriers for URM Students in Dermatology

Multiple studies have attempted to identify some of the barriers faced by URM students in medicine that might explain the lack of diversity in competitive specialties. Vasquez and colleagues⁴ identified 4 major factors that play a role in dermatology: lack of equitable resources, lack of support, financial limitations, and the lack of group identity. More than half of URM students surveyed (1) identified lack of support as a barrier and (2) reported having been encouraged to seek a specialty more reflective of their community.⁴

Soliman et al⁵ reported that URM barriers in dermatology extend to include lack of diversity in the field, socioeconomic factors, lack of mentorship, and a negative perception of minority students by residency programs. Dermatology is the second least diverse specialty in medicine after orthopedic surgery, which, in and of itself, might further discourage URM students from applying to dermatology.⁵

With the minimal exposure that URM students have to the field of dermatology, the lack of pipeline programs, and reports that URMs often are encouraged to pursue primary care, the current diversity deficiency in dermatology comes as no surprise. In addition, the substantial disadvantage for URM students is perpetuated by the traditional highly selective process that favors grades, board scores, and honor society status over holistic assessment of the individual student and their unique experiences and potential for contribution.

Looking Beyond Test Scores

The US Medical Licensing Examination (USMLE) traditionally has been used to select dermatology residency applicants, with high cutoff scores often excluding outstanding URM students. Research has suggested that the use of USMLE examination test scores for residency recruitment lacks validity because it has poor predictability of residency performance.⁶ Although the USMLE Step 1 examination is transitioning to pass/fail scoring, applicants for the next cycle will still have a 3-digit numerical score.

We strongly recommend that dermatology programs transition from emphasizing scores of residency candidates to reviewing each candidate holistically. The AAMC defines “holistic review” as a “flexible, individualized way of assessing an applicant’s capabilities, by which balanced consideration is given to experiences, attributes, competencies, and academic or scholarly metrics and, when considered in combination, how the individual might contribute value to the institution’s mission.”⁷ Furthermore, we recommend that dermatology residency programs have multiple faculty members review each application, including a representative of the diversity, inclusion, and equity committee.

In the COVID-19 era, dermatology externship opportunities that would have allowed URM students to work directly with potential residency programs, showcase their abilities, and network have been limited. Virtual residency interviews could make it more challenging to evaluate candidates, especially URM students from less prestigious programs or unusual socioeconomic backgrounds, or with lower board scores. In addition, virtual interviews can more easily become one-dimensional, depriving URM students of the opportunity to gauge their personal fit in a specific dermatology residency program and its community. Questions and concerns of URM students might include: Will I be appropriately supported and mentored? Will my cultural preferences, religion, sexual preference, hairstyle, and beliefs be accepted? Can I advocate for minorities and support antiracism and diversity and inclusion initiatives? To that end, we recommend that dermatology programs continue to host virtual meet-and-greet events for potential students to meet faculty and learn more about the program. In addition, programs should consider having current residents interact virtually with candidates to allow students to better understand the culture of the department and residents’ experiences as trainees in such an environment. For URM students, this is highly important because diversity, inclusion, and antiracism policies and initiatives might not be explicitly available on the institution’s website or residency information page.

Organizations Championing Diversity

Recently, multiple dermatology societies and organizations have been emphasizing the need for diversity and inclusion as well as promoting holistic application review. The American Academy of Dermatology pioneered the Diversity Champion Workshop in 2019 and continues to offer the Diversity Mentorship program, connecting URM students to mentors nationally. The Skin of Color Society offers yearly grants and awards to medical students to develop mentorship and research, and recently hosted webinars to guide medical students and residency programs on diversity and inclusion, residency application and review, and COVID-19 virtual interviews. Other national societies, such as the Student National Medical Association and Latino Medical Student Association, have been promoting workshops and interview mentoring for URM students, including dermatology-specific events. Although it is estimated that more than 90% of medical schools in the United States already perform holistic application review and that such review has been adopted by many dermatology programs nationwide, data regarding dermatology residency programs’ implementation of holistic application review are lacking.⁸

In addition, we encourage continuation of the proposed coordinated interview invite release from the Association of Professors of Dermatology, which was implemented in the 2020-2021 cycle. In light of the recent AAMC letter⁹ on the maldistribution of interview invitations to highest-tier applicants, coordination of interview release dates and other similar initiatives to prevent programs from offering more invites than their available slots and improve transparency about interview days are needed. Furthermore, continuing to offer optional virtual interviews for applicants in future cycles could make the process less cost-prohibitive for many URM students.^4,5

Final Thoughts

Dermatology residency programs must intentionally guard against falling back to traditional standards of assessment as the only means of student evaluation, especially in this virtual era. It is our responsibility to remove artificial barriers that continue to stall progress in diversity, inclusion, equity, and belonging in dermatology.

The COVID-19 pandemic has markedly changed the dermatology residency application process. As medical students head into this application cycle, the impacts of systemic racism and deeply rooted structural barriers continue to be exacerbated for students who identify as an underrepresented minority (URM) in medicine—historically defined as those who self-identify as Hispanic or Latinx; Black or African American; American Indian or Alaska Native; or Native Hawaiian or Pacific Islander. The Association of American Medical Colleges (AAMC) defines URMs as racial and ethnic populations that are underrepresented in medicine relative to their numbers in the general population.¹ Although these groups account for approximately 34% of the population of the United States, they constitute only 11% of the country’s physician workforce.^2,3

Of the total physician workforce in the United States, Black and African American physicians account for 5% of practicing physicians; Hispanic physicians, 5.8%; American Indian and Alaska Native physicians, 0.3%; and Native Hawaiian and Pacific Islander physicians, 0.1%.² In competitive medical specialties, the disproportionality of these numbers compared to our current demographics in the United States as shown above is even more staggering. In 2018, for example, 10% of practicing dermatologists identified as female URM physicians; 6%, as male URM physicians.² In this article, we discuss some of the challenges and considerations for URM students applying to dermatology residency in the era of the COVID-19 pandemic.

Barriers for URM Students in Dermatology

Multiple studies have attempted to identify some of the barriers faced by URM students in medicine that might explain the lack of diversity in competitive specialties. Vasquez and colleagues⁴ identified 4 major factors that play a role in dermatology: lack of equitable resources, lack of support, financial limitations, and the lack of group identity. More than half of URM students surveyed (1) identified lack of support as a barrier and (2) reported having been encouraged to seek a specialty more reflective of their community.⁴

Soliman et al⁵ reported that URM barriers in dermatology extend to include lack of diversity in the field, socioeconomic factors, lack of mentorship, and a negative perception of minority students by residency programs. Dermatology is the second least diverse specialty in medicine after orthopedic surgery, which, in and of itself, might further discourage URM students from applying to dermatology.⁵

With the minimal exposure that URM students have to the field of dermatology, the lack of pipeline programs, and reports that URMs often are encouraged to pursue primary care, the current diversity deficiency in dermatology comes as no surprise. In addition, the substantial disadvantage for URM students is perpetuated by the traditional highly selective process that favors grades, board scores, and honor society status over holistic assessment of the individual student and their unique experiences and potential for contribution.

Looking Beyond Test Scores

The US Medical Licensing Examination (USMLE) traditionally has been used to select dermatology residency applicants, with high cutoff scores often excluding outstanding URM students. Research has suggested that the use of USMLE examination test scores for residency recruitment lacks validity because it has poor predictability of residency performance.⁶ Although the USMLE Step 1 examination is transitioning to pass/fail scoring, applicants for the next cycle will still have a 3-digit numerical score.

We strongly recommend that dermatology programs transition from emphasizing scores of residency candidates to reviewing each candidate holistically. The AAMC defines “holistic review” as a “flexible, individualized way of assessing an applicant’s capabilities, by which balanced consideration is given to experiences, attributes, competencies, and academic or scholarly metrics and, when considered in combination, how the individual might contribute value to the institution’s mission.”⁷ Furthermore, we recommend that dermatology residency programs have multiple faculty members review each application, including a representative of the diversity, inclusion, and equity committee.

In the COVID-19 era, dermatology externship opportunities that would have allowed URM students to work directly with potential residency programs, showcase their abilities, and network have been limited. Virtual residency interviews could make it more challenging to evaluate candidates, especially URM students from less prestigious programs or unusual socioeconomic backgrounds, or with lower board scores. In addition, virtual interviews can more easily become one-dimensional, depriving URM students of the opportunity to gauge their personal fit in a specific dermatology residency program and its community. Questions and concerns of URM students might include: Will I be appropriately supported and mentored? Will my cultural preferences, religion, sexual preference, hairstyle, and beliefs be accepted? Can I advocate for minorities and support antiracism and diversity and inclusion initiatives? To that end, we recommend that dermatology programs continue to host virtual meet-and-greet events for potential students to meet faculty and learn more about the program. In addition, programs should consider having current residents interact virtually with candidates to allow students to better understand the culture of the department and residents’ experiences as trainees in such an environment. For URM students, this is highly important because diversity, inclusion, and antiracism policies and initiatives might not be explicitly available on the institution’s website or residency information page.

Organizations Championing Diversity

Recently, multiple dermatology societies and organizations have been emphasizing the need for diversity and inclusion as well as promoting holistic application review. The American Academy of Dermatology pioneered the Diversity Champion Workshop in 2019 and continues to offer the Diversity Mentorship program, connecting URM students to mentors nationally. The Skin of Color Society offers yearly grants and awards to medical students to develop mentorship and research, and recently hosted webinars to guide medical students and residency programs on diversity and inclusion, residency application and review, and COVID-19 virtual interviews. Other national societies, such as the Student National Medical Association and Latino Medical Student Association, have been promoting workshops and interview mentoring for URM students, including dermatology-specific events. Although it is estimated that more than 90% of medical schools in the United States already perform holistic application review and that such review has been adopted by many dermatology programs nationwide, data regarding dermatology residency programs’ implementation of holistic application review are lacking.⁸

In addition, we encourage continuation of the proposed coordinated interview invite release from the Association of Professors of Dermatology, which was implemented in the 2020-2021 cycle. In light of the recent AAMC letter⁹ on the maldistribution of interview invitations to highest-tier applicants, coordination of interview release dates and other similar initiatives to prevent programs from offering more invites than their available slots and improve transparency about interview days are needed. Furthermore, continuing to offer optional virtual interviews for applicants in future cycles could make the process less cost-prohibitive for many URM students.^4,5

Final Thoughts

Dermatology residency programs must intentionally guard against falling back to traditional standards of assessment as the only means of student evaluation, especially in this virtual era. It is our responsibility to remove artificial barriers that continue to stall progress in diversity, inclusion, equity, and belonging in dermatology.