MDedge Dermatology

THE DIAGNOSIS: Gouty Tophus

The lesion was excised and sent for histopathologic examination (eFigures 1 and 2), revealing aggregates of feathery, amorphous, pale-pink material, which confirmed the diagnosis of gouty tophus. The surgical site was left to heal by secondary intention. Upon further evaluation, the patient reported recurrent monoarticular joint pain in the ankles and feet, and laboratory workup revealed elevated serum uric acid. He was advised to follow up with his primary care physician to discuss systemic treatment options for gout.

Gout is an inflammatory arthritis characterized by the deposition of monosodium urate monohydrate crystals in the joints, soft tissue, and bone due to elevated serum uric acid. Uric acid is the final product of purine metabolism, and serum levels may be elevated due to excess production or underexcretion. Multiple genetic, environmental, and metabolic factors influence these processes.¹ Collections of monosodium urate crystals may develop intra- or extra-articularly, the latter of which are known as gouty tophi. These nodules have a classic chalklike consistency and typically are seen in patients with untreated gout starting approximately 10 years after the first flare. The most common locations for subcutaneous gouty tophi are acral sites (eg, fingertips, ears) as well as the wrists, knees, and elbows (olecranon bursae). Rarely, gouty panniculitis also may develop.²

Histopathology of gouty tophi reveals nodular aggregates of acellular, amorphous, pale-pink material surrounded by palisading histiocytes and multinucleated giant cells. The presence of needlelike monosodium urate crystals, which display negative birefringence, is diagnostic. Unfortunately, these crystals are destroyed in routine formalin processing.³

There are limited data regarding treatment of gouty tophi. Urate-lowering systemic medications such as pegloticase may be beneficial, but more data are needed.⁴ We pursued surgical excision in our case for definitive diagnosis; however, it is not a common treatment for gouty tophi. Typically, urate-lowering therapy is utilized to resolve or shrink lesions over time.⁵

The differential diagnosis for gouty tophi includes epidermal inclusion cyst (EIC), the most common type of cutaneous cyst. Though EICs can manifest anywhere on the body, they are not as common on the ears as gouty tophi. Epidermal inclusion cysts clinically manifest as soft subcutaneous nodules, and a central punctum often is noted. These lesions are derived from the follicular infundibulum and histologically are characterized by a cystic cavity lined by a stratified squamous epithelium with a granular layer. The cavity contains loose laminated keratin material.⁶

Pseudocyst of the auricle is a benign cystic swelling of the pinna that can develop spontaneously but most often manifests following trauma to the area, which is believed to separate the tissue planes in the cartilage, allowing fluid to accumulate. This lesion typically is asymptomatic, though some patients report mild tenderness.⁷ Histology shows a cystic structure within the cartilage without an epithelial lining, and a perivascular inflammatory response often is observed.⁸

Pilomatricoma, also known as pilomatrixoma, is a benign tumor derived from the hair follicle matrix that manifests as a firm, slow-growing, painless subcutaneous nodule. It most often is found on the head and neck, commonly in the periauricular area.⁹ Though rare, it has been found on the auricle and external auditory canal.¹⁰ Histologically, pilomatricomas are well-defined tumors containing internal trabeculae. They contain populations of basaloid and ghost cells and often calcify, sometimes with resultant bone formation.⁹

Dermoid cysts are benign tumors that develop along lines of embryonic closure and often are diagnosed at birth or in early childhood. They most commonly manifest on the head and neck, typically in the supraorbital area. Rarely, they have been reported on the ear.⁶ Dermoid cysts may resemble EICs clinically and histopathologically, except that the cyst wall contains mature adnexal structures such as hair follicles and sebaceous glands.

THE DIAGNOSIS: Gouty Tophus

The lesion was excised and sent for histopathologic examination (eFigures 1 and 2), revealing aggregates of feathery, amorphous, pale-pink material, which confirmed the diagnosis of gouty tophus. The surgical site was left to heal by secondary intention. Upon further evaluation, the patient reported recurrent monoarticular joint pain in the ankles and feet, and laboratory workup revealed elevated serum uric acid. He was advised to follow up with his primary care physician to discuss systemic treatment options for gout.

Gout is an inflammatory arthritis characterized by the deposition of monosodium urate monohydrate crystals in the joints, soft tissue, and bone due to elevated serum uric acid. Uric acid is the final product of purine metabolism, and serum levels may be elevated due to excess production or underexcretion. Multiple genetic, environmental, and metabolic factors influence these processes.¹ Collections of monosodium urate crystals may develop intra- or extra-articularly, the latter of which are known as gouty tophi. These nodules have a classic chalklike consistency and typically are seen in patients with untreated gout starting approximately 10 years after the first flare. The most common locations for subcutaneous gouty tophi are acral sites (eg, fingertips, ears) as well as the wrists, knees, and elbows (olecranon bursae). Rarely, gouty panniculitis also may develop.²

Histopathology of gouty tophi reveals nodular aggregates of acellular, amorphous, pale-pink material surrounded by palisading histiocytes and multinucleated giant cells. The presence of needlelike monosodium urate crystals, which display negative birefringence, is diagnostic. Unfortunately, these crystals are destroyed in routine formalin processing.³

There are limited data regarding treatment of gouty tophi. Urate-lowering systemic medications such as pegloticase may be beneficial, but more data are needed.⁴ We pursued surgical excision in our case for definitive diagnosis; however, it is not a common treatment for gouty tophi. Typically, urate-lowering therapy is utilized to resolve or shrink lesions over time.⁵

The differential diagnosis for gouty tophi includes epidermal inclusion cyst (EIC), the most common type of cutaneous cyst. Though EICs can manifest anywhere on the body, they are not as common on the ears as gouty tophi. Epidermal inclusion cysts clinically manifest as soft subcutaneous nodules, and a central punctum often is noted. These lesions are derived from the follicular infundibulum and histologically are characterized by a cystic cavity lined by a stratified squamous epithelium with a granular layer. The cavity contains loose laminated keratin material.⁶

Pseudocyst of the auricle is a benign cystic swelling of the pinna that can develop spontaneously but most often manifests following trauma to the area, which is believed to separate the tissue planes in the cartilage, allowing fluid to accumulate. This lesion typically is asymptomatic, though some patients report mild tenderness.⁷ Histology shows a cystic structure within the cartilage without an epithelial lining, and a perivascular inflammatory response often is observed.⁸

Pilomatricoma, also known as pilomatrixoma, is a benign tumor derived from the hair follicle matrix that manifests as a firm, slow-growing, painless subcutaneous nodule. It most often is found on the head and neck, commonly in the periauricular area.⁹ Though rare, it has been found on the auricle and external auditory canal.¹⁰ Histologically, pilomatricomas are well-defined tumors containing internal trabeculae. They contain populations of basaloid and ghost cells and often calcify, sometimes with resultant bone formation.⁹

Dermoid cysts are benign tumors that develop along lines of embryonic closure and often are diagnosed at birth or in early childhood. They most commonly manifest on the head and neck, typically in the supraorbital area. Rarely, they have been reported on the ear.⁶ Dermoid cysts may resemble EICs clinically and histopathologically, except that the cyst wall contains mature adnexal structures such as hair follicles and sebaceous glands.

THE DIAGNOSIS: Gouty Tophus

The lesion was excised and sent for histopathologic examination (eFigures 1 and 2), revealing aggregates of feathery, amorphous, pale-pink material, which confirmed the diagnosis of gouty tophus. The surgical site was left to heal by secondary intention. Upon further evaluation, the patient reported recurrent monoarticular joint pain in the ankles and feet, and laboratory workup revealed elevated serum uric acid. He was advised to follow up with his primary care physician to discuss systemic treatment options for gout.

Gout is an inflammatory arthritis characterized by the deposition of monosodium urate monohydrate crystals in the joints, soft tissue, and bone due to elevated serum uric acid. Uric acid is the final product of purine metabolism, and serum levels may be elevated due to excess production or underexcretion. Multiple genetic, environmental, and metabolic factors influence these processes.¹ Collections of monosodium urate crystals may develop intra- or extra-articularly, the latter of which are known as gouty tophi. These nodules have a classic chalklike consistency and typically are seen in patients with untreated gout starting approximately 10 years after the first flare. The most common locations for subcutaneous gouty tophi are acral sites (eg, fingertips, ears) as well as the wrists, knees, and elbows (olecranon bursae). Rarely, gouty panniculitis also may develop.²

Histopathology of gouty tophi reveals nodular aggregates of acellular, amorphous, pale-pink material surrounded by palisading histiocytes and multinucleated giant cells. The presence of needlelike monosodium urate crystals, which display negative birefringence, is diagnostic. Unfortunately, these crystals are destroyed in routine formalin processing.³

There are limited data regarding treatment of gouty tophi. Urate-lowering systemic medications such as pegloticase may be beneficial, but more data are needed.⁴ We pursued surgical excision in our case for definitive diagnosis; however, it is not a common treatment for gouty tophi. Typically, urate-lowering therapy is utilized to resolve or shrink lesions over time.⁵

The differential diagnosis for gouty tophi includes epidermal inclusion cyst (EIC), the most common type of cutaneous cyst. Though EICs can manifest anywhere on the body, they are not as common on the ears as gouty tophi. Epidermal inclusion cysts clinically manifest as soft subcutaneous nodules, and a central punctum often is noted. These lesions are derived from the follicular infundibulum and histologically are characterized by a cystic cavity lined by a stratified squamous epithelium with a granular layer. The cavity contains loose laminated keratin material.⁶

Pseudocyst of the auricle is a benign cystic swelling of the pinna that can develop spontaneously but most often manifests following trauma to the area, which is believed to separate the tissue planes in the cartilage, allowing fluid to accumulate. This lesion typically is asymptomatic, though some patients report mild tenderness.⁷ Histology shows a cystic structure within the cartilage without an epithelial lining, and a perivascular inflammatory response often is observed.⁸

Pilomatricoma, also known as pilomatrixoma, is a benign tumor derived from the hair follicle matrix that manifests as a firm, slow-growing, painless subcutaneous nodule. It most often is found on the head and neck, commonly in the periauricular area.⁹ Though rare, it has been found on the auricle and external auditory canal.¹⁰ Histologically, pilomatricomas are well-defined tumors containing internal trabeculae. They contain populations of basaloid and ghost cells and often calcify, sometimes with resultant bone formation.⁹

Dermoid cysts are benign tumors that develop along lines of embryonic closure and often are diagnosed at birth or in early childhood. They most commonly manifest on the head and neck, typically in the supraorbital area. Rarely, they have been reported on the ear.⁶ Dermoid cysts may resemble EICs clinically and histopathologically, except that the cyst wall contains mature adnexal structures such as hair follicles and sebaceous glands.

THE DIAGNOSIS: Lepromatous Leprosy

Histopathology showed collections of epithelioid to sarcoidal granulomas throughout the dermis and clustered around nerve bundles with a grenz zone at the dermoepidermal junction. Fite stain was positive for acid-fast bacteria, which were confirmed to be Mycobacterium leprae by by the National Hansen’s Disease program. Based on these findings, a diagnosis of lepromatous leprosy (LL) was made. The patient was treated by the infectious disease department with multidrug therapy that included monthly rifampin, moxifloxacin, and minocycline; weekly methotrexate with daily folic acid; and an extended prednisone taper with prophylactic cholecalciferol.

Lepromatous leprosy is characterized by high antibody titers to the acid-fast, gram-positive bacillus Mycobacterium leprae as well as a high bacillary load.¹ Patients typically present with muscle weakness, anesthetic skin patches, and claw hands. Patients also may present with foot drop, ulcerations of the hands and feet, autonomic dysfunction with anhidrosis or impaired sweating, and localized alopecia.² Over months to years, LL may progress to extensive sensory loss and indurated lesions that infiltrate the skin and cause thickening, especially on the face (known as leonine facies). Furthermore, LL is characterized by extensive bilaterally symmetric cutaneous lesions with poorly defined borders and raised indurated centers.³

Lepromatous leprosy transmission is not fully understood but is thought to occur via airborne droplets from coughing/sneezing and nasal secretions.² Histopathology generally shows a dense and diffuse granulomatous infiltrate that involves the dermis but is separated from the epidermis by a zone of collagen (grenz zone).³ Histology is characterized by the presence of lymphocytes and numerous foamy macrophages (lepra or Virchow cells) containing M leprae organisms. In persistent lesions, the high density of uncleared bacilli forms spherical cytoplasmic clumps known as globi within enlarged foamy histiocytes (Figure 1).⁴ The macrophages form granulomatous lesions in the skin and around nerve bundles, resulting in tissue damage and decreased sensation. The current standard of care for LL is a multidrug combination of dapsone, rifampin, and clofazimine. Early diagnosis and complete treatment of LL is crucial, as this approach typically leads to complete cure of the disease.

The differential diagnosis for LL includes granuloma annulare (GA), mycosis fungoides (MF), sarcoidosis, and subacute cutaneous lupus erythematosus (SCLE). Granuloma annulare is a noninfectious inflammatory granulomatous skin disease that manifests in a localized, generalized, or subcutaneous pattern. Localized GA is the most common form and manifests as self-resolving, flesh-colored or erythematous papules or plaques limited to the extremities.^5,6 Generalized GA is defined by more than 10 widespread annular plaques involving the trunk and extremities and can persist for decades.⁶ This form can be associated with hyperlipidemia, diabetes, autoimmune disease and immunodeficiency (eg, HIV), and rarely with lymphoma or solid tumors. On histology, GA shows necrobiosis surrounded by palisading histiocytes and mucin (palisading GA) or patchy interstitial histiocytes and lymphocytes (interstitial GA)(Figure 2).⁶ This palisading pattern differs from the histiocytes in LL, which contain numerous acid-fast bacilli and bacterial clumps. Topical and intralesional corticosteroids are first-line therapies for GA.

Mycosis fungoides is a cutaneous T-cell lymphoma characterized by proliferation of CD4+ T cells.⁷ In the early stages of MF, patients may present with multiple erythematous and scaly patches, plaques, or nodules that most commonly develop on unexposed areas of the skin, but specific variants frequently may cause lesions on the face or scalp.⁸ Tumors may be solitary, localized, or generalized and may be observed alongside patches and plaques or in the absence of cutaneous lesions.⁷ The pathologic features of MF include fibrosis of the papillary dermis, individual haloed atypical lymphocytes in the epidermis, and atypical lymphoid cells with cerebriform nuclei (Figure 3).⁹ Granulomatous MF is characterized by diffuse nodular and perivascular infiltrates of histiocytes with small lymphocytes without atypia, eosinophils, and plasma cells. Small lymphocytes with cerebriform nuclei and larger lymphocytes with hyperconvoluted nuclei also may be seen, in addition to multinucleated histiocytic giant cells. Although MF commonly manifests with epidermotropism, it typically is absent in granulomatous MF (GMF).¹⁰ Granulomatous MF may manifest similarly to LL. Noduloulcerative lesions and infiltration of atypical lymphocytes into the epidermis (epidermotropism) are much more common in GMF than in LL; however, although ulcerative nodules are not a common feature in patients with leprosy (except during reactional states [ie, Lucio phenomenon]) or secondary to neuropathies, they also can occur in LL.¹¹ In GMF, the infiltrate does not follow a specific pattern, whereas LL infiltrates tend to follow a nerve distribution. Treatment for MF is determined by disease severity.¹² First-line therapy includes local corticosteroids and phototherapy with UVB irradiation.

Sarcoidosis is a multisystem disease that demonstrates nonspecific clinical manifestations affecting the lungs, eyes, liver, and skin.¹³ Environmental exposures to silica and inorganic matter have been linked to an increased risk for sarcoidosis, with patients presenting with fatigue, fever, and arthralgia.¹³ Skin manifestations include subcutaneous nodules, polymorphous plaques, and erythema nodosum—nodosum—the most common cutaneous presentation of sarcoidosis. Erythema nodosum manifests as symmetrically distributed, nonulcerative, painful red nodules on the skin, especially the lower legs. The histopathology of sarcoidosis shows noncaseating granulomas with activated T-lymphocytes, epithelioid cells, and multinucleated giant cells (Figure 4). Although granulomas occur in both LL and sarcoidosis, those in sarcoidosis typically consist of epithelioid cells surrounded by a rim of lymphocytes, whereas LL granulomas contain foamy histiocytes and multinucleated giant cells. Treatment of sarcoidosis depends on disease progression and generally involves oral corticosteroids, followed by corticosteroid-sparing regimens.

Subacute cutaneous lupus erythematosus is a chronic autoimmune disease that predominantly affects younger women. Common findings in SCLE include red scaly plaques and ring-shaped lesions on sun-exposed areas of the skin.¹⁴ Subacute cutaneous lupus erythematosus primarily is characterized by a photosensitive rash, often with arthralgia, myalgia, and/or oral ulcers; less commonly, a small percentage of patients can experience central nervous system involvement, vasculitis, or nephritis. The histologic findings of SCLE include hydropic degeneration of the basal cell layer and periadnexal infiltrates (Figure 5). The incidence of SCLE often is associated with anti-Ro (SSA) and anti-La (SSB) antibodies.¹⁵ Treatment of SCLE focuses on managing skin symptoms with corticosteroids, antimalarials, and sun protection.

THE DIAGNOSIS: Lepromatous Leprosy

Histopathology showed collections of epithelioid to sarcoidal granulomas throughout the dermis and clustered around nerve bundles with a grenz zone at the dermoepidermal junction. Fite stain was positive for acid-fast bacteria, which were confirmed to be Mycobacterium leprae by by the National Hansen’s Disease program. Based on these findings, a diagnosis of lepromatous leprosy (LL) was made. The patient was treated by the infectious disease department with multidrug therapy that included monthly rifampin, moxifloxacin, and minocycline; weekly methotrexate with daily folic acid; and an extended prednisone taper with prophylactic cholecalciferol.

Lepromatous leprosy is characterized by high antibody titers to the acid-fast, gram-positive bacillus Mycobacterium leprae as well as a high bacillary load.¹ Patients typically present with muscle weakness, anesthetic skin patches, and claw hands. Patients also may present with foot drop, ulcerations of the hands and feet, autonomic dysfunction with anhidrosis or impaired sweating, and localized alopecia.² Over months to years, LL may progress to extensive sensory loss and indurated lesions that infiltrate the skin and cause thickening, especially on the face (known as leonine facies). Furthermore, LL is characterized by extensive bilaterally symmetric cutaneous lesions with poorly defined borders and raised indurated centers.³

Lepromatous leprosy transmission is not fully understood but is thought to occur via airborne droplets from coughing/sneezing and nasal secretions.² Histopathology generally shows a dense and diffuse granulomatous infiltrate that involves the dermis but is separated from the epidermis by a zone of collagen (grenz zone).³ Histology is characterized by the presence of lymphocytes and numerous foamy macrophages (lepra or Virchow cells) containing M leprae organisms. In persistent lesions, the high density of uncleared bacilli forms spherical cytoplasmic clumps known as globi within enlarged foamy histiocytes (Figure 1).⁴ The macrophages form granulomatous lesions in the skin and around nerve bundles, resulting in tissue damage and decreased sensation. The current standard of care for LL is a multidrug combination of dapsone, rifampin, and clofazimine. Early diagnosis and complete treatment of LL is crucial, as this approach typically leads to complete cure of the disease.

The differential diagnosis for LL includes granuloma annulare (GA), mycosis fungoides (MF), sarcoidosis, and subacute cutaneous lupus erythematosus (SCLE). Granuloma annulare is a noninfectious inflammatory granulomatous skin disease that manifests in a localized, generalized, or subcutaneous pattern. Localized GA is the most common form and manifests as self-resolving, flesh-colored or erythematous papules or plaques limited to the extremities.^5,6 Generalized GA is defined by more than 10 widespread annular plaques involving the trunk and extremities and can persist for decades.⁶ This form can be associated with hyperlipidemia, diabetes, autoimmune disease and immunodeficiency (eg, HIV), and rarely with lymphoma or solid tumors. On histology, GA shows necrobiosis surrounded by palisading histiocytes and mucin (palisading GA) or patchy interstitial histiocytes and lymphocytes (interstitial GA)(Figure 2).⁶ This palisading pattern differs from the histiocytes in LL, which contain numerous acid-fast bacilli and bacterial clumps. Topical and intralesional corticosteroids are first-line therapies for GA.

Mycosis fungoides is a cutaneous T-cell lymphoma characterized by proliferation of CD4+ T cells.⁷ In the early stages of MF, patients may present with multiple erythematous and scaly patches, plaques, or nodules that most commonly develop on unexposed areas of the skin, but specific variants frequently may cause lesions on the face or scalp.⁸ Tumors may be solitary, localized, or generalized and may be observed alongside patches and plaques or in the absence of cutaneous lesions.⁷ The pathologic features of MF include fibrosis of the papillary dermis, individual haloed atypical lymphocytes in the epidermis, and atypical lymphoid cells with cerebriform nuclei (Figure 3).⁹ Granulomatous MF is characterized by diffuse nodular and perivascular infiltrates of histiocytes with small lymphocytes without atypia, eosinophils, and plasma cells. Small lymphocytes with cerebriform nuclei and larger lymphocytes with hyperconvoluted nuclei also may be seen, in addition to multinucleated histiocytic giant cells. Although MF commonly manifests with epidermotropism, it typically is absent in granulomatous MF (GMF).¹⁰ Granulomatous MF may manifest similarly to LL. Noduloulcerative lesions and infiltration of atypical lymphocytes into the epidermis (epidermotropism) are much more common in GMF than in LL; however, although ulcerative nodules are not a common feature in patients with leprosy (except during reactional states [ie, Lucio phenomenon]) or secondary to neuropathies, they also can occur in LL.¹¹ In GMF, the infiltrate does not follow a specific pattern, whereas LL infiltrates tend to follow a nerve distribution. Treatment for MF is determined by disease severity.¹² First-line therapy includes local corticosteroids and phototherapy with UVB irradiation.

Sarcoidosis is a multisystem disease that demonstrates nonspecific clinical manifestations affecting the lungs, eyes, liver, and skin.¹³ Environmental exposures to silica and inorganic matter have been linked to an increased risk for sarcoidosis, with patients presenting with fatigue, fever, and arthralgia.¹³ Skin manifestations include subcutaneous nodules, polymorphous plaques, and erythema nodosum—nodosum—the most common cutaneous presentation of sarcoidosis. Erythema nodosum manifests as symmetrically distributed, nonulcerative, painful red nodules on the skin, especially the lower legs. The histopathology of sarcoidosis shows noncaseating granulomas with activated T-lymphocytes, epithelioid cells, and multinucleated giant cells (Figure 4). Although granulomas occur in both LL and sarcoidosis, those in sarcoidosis typically consist of epithelioid cells surrounded by a rim of lymphocytes, whereas LL granulomas contain foamy histiocytes and multinucleated giant cells. Treatment of sarcoidosis depends on disease progression and generally involves oral corticosteroids, followed by corticosteroid-sparing regimens.

Subacute cutaneous lupus erythematosus is a chronic autoimmune disease that predominantly affects younger women. Common findings in SCLE include red scaly plaques and ring-shaped lesions on sun-exposed areas of the skin.¹⁴ Subacute cutaneous lupus erythematosus primarily is characterized by a photosensitive rash, often with arthralgia, myalgia, and/or oral ulcers; less commonly, a small percentage of patients can experience central nervous system involvement, vasculitis, or nephritis. The histologic findings of SCLE include hydropic degeneration of the basal cell layer and periadnexal infiltrates (Figure 5). The incidence of SCLE often is associated with anti-Ro (SSA) and anti-La (SSB) antibodies.¹⁵ Treatment of SCLE focuses on managing skin symptoms with corticosteroids, antimalarials, and sun protection.

THE DIAGNOSIS: Lepromatous Leprosy

Histopathology showed collections of epithelioid to sarcoidal granulomas throughout the dermis and clustered around nerve bundles with a grenz zone at the dermoepidermal junction. Fite stain was positive for acid-fast bacteria, which were confirmed to be Mycobacterium leprae by by the National Hansen’s Disease program. Based on these findings, a diagnosis of lepromatous leprosy (LL) was made. The patient was treated by the infectious disease department with multidrug therapy that included monthly rifampin, moxifloxacin, and minocycline; weekly methotrexate with daily folic acid; and an extended prednisone taper with prophylactic cholecalciferol.

Lepromatous leprosy is characterized by high antibody titers to the acid-fast, gram-positive bacillus Mycobacterium leprae as well as a high bacillary load.¹ Patients typically present with muscle weakness, anesthetic skin patches, and claw hands. Patients also may present with foot drop, ulcerations of the hands and feet, autonomic dysfunction with anhidrosis or impaired sweating, and localized alopecia.² Over months to years, LL may progress to extensive sensory loss and indurated lesions that infiltrate the skin and cause thickening, especially on the face (known as leonine facies). Furthermore, LL is characterized by extensive bilaterally symmetric cutaneous lesions with poorly defined borders and raised indurated centers.³

Lepromatous leprosy transmission is not fully understood but is thought to occur via airborne droplets from coughing/sneezing and nasal secretions.² Histopathology generally shows a dense and diffuse granulomatous infiltrate that involves the dermis but is separated from the epidermis by a zone of collagen (grenz zone).³ Histology is characterized by the presence of lymphocytes and numerous foamy macrophages (lepra or Virchow cells) containing M leprae organisms. In persistent lesions, the high density of uncleared bacilli forms spherical cytoplasmic clumps known as globi within enlarged foamy histiocytes (Figure 1).⁴ The macrophages form granulomatous lesions in the skin and around nerve bundles, resulting in tissue damage and decreased sensation. The current standard of care for LL is a multidrug combination of dapsone, rifampin, and clofazimine. Early diagnosis and complete treatment of LL is crucial, as this approach typically leads to complete cure of the disease.

The differential diagnosis for LL includes granuloma annulare (GA), mycosis fungoides (MF), sarcoidosis, and subacute cutaneous lupus erythematosus (SCLE). Granuloma annulare is a noninfectious inflammatory granulomatous skin disease that manifests in a localized, generalized, or subcutaneous pattern. Localized GA is the most common form and manifests as self-resolving, flesh-colored or erythematous papules or plaques limited to the extremities.^5,6 Generalized GA is defined by more than 10 widespread annular plaques involving the trunk and extremities and can persist for decades.⁶ This form can be associated with hyperlipidemia, diabetes, autoimmune disease and immunodeficiency (eg, HIV), and rarely with lymphoma or solid tumors. On histology, GA shows necrobiosis surrounded by palisading histiocytes and mucin (palisading GA) or patchy interstitial histiocytes and lymphocytes (interstitial GA)(Figure 2).⁶ This palisading pattern differs from the histiocytes in LL, which contain numerous acid-fast bacilli and bacterial clumps. Topical and intralesional corticosteroids are first-line therapies for GA.

Mycosis fungoides is a cutaneous T-cell lymphoma characterized by proliferation of CD4+ T cells.⁷ In the early stages of MF, patients may present with multiple erythematous and scaly patches, plaques, or nodules that most commonly develop on unexposed areas of the skin, but specific variants frequently may cause lesions on the face or scalp.⁸ Tumors may be solitary, localized, or generalized and may be observed alongside patches and plaques or in the absence of cutaneous lesions.⁷ The pathologic features of MF include fibrosis of the papillary dermis, individual haloed atypical lymphocytes in the epidermis, and atypical lymphoid cells with cerebriform nuclei (Figure 3).⁹ Granulomatous MF is characterized by diffuse nodular and perivascular infiltrates of histiocytes with small lymphocytes without atypia, eosinophils, and plasma cells. Small lymphocytes with cerebriform nuclei and larger lymphocytes with hyperconvoluted nuclei also may be seen, in addition to multinucleated histiocytic giant cells. Although MF commonly manifests with epidermotropism, it typically is absent in granulomatous MF (GMF).¹⁰ Granulomatous MF may manifest similarly to LL. Noduloulcerative lesions and infiltration of atypical lymphocytes into the epidermis (epidermotropism) are much more common in GMF than in LL; however, although ulcerative nodules are not a common feature in patients with leprosy (except during reactional states [ie, Lucio phenomenon]) or secondary to neuropathies, they also can occur in LL.¹¹ In GMF, the infiltrate does not follow a specific pattern, whereas LL infiltrates tend to follow a nerve distribution. Treatment for MF is determined by disease severity.¹² First-line therapy includes local corticosteroids and phototherapy with UVB irradiation.

Sarcoidosis is a multisystem disease that demonstrates nonspecific clinical manifestations affecting the lungs, eyes, liver, and skin.¹³ Environmental exposures to silica and inorganic matter have been linked to an increased risk for sarcoidosis, with patients presenting with fatigue, fever, and arthralgia.¹³ Skin manifestations include subcutaneous nodules, polymorphous plaques, and erythema nodosum—nodosum—the most common cutaneous presentation of sarcoidosis. Erythema nodosum manifests as symmetrically distributed, nonulcerative, painful red nodules on the skin, especially the lower legs. The histopathology of sarcoidosis shows noncaseating granulomas with activated T-lymphocytes, epithelioid cells, and multinucleated giant cells (Figure 4). Although granulomas occur in both LL and sarcoidosis, those in sarcoidosis typically consist of epithelioid cells surrounded by a rim of lymphocytes, whereas LL granulomas contain foamy histiocytes and multinucleated giant cells. Treatment of sarcoidosis depends on disease progression and generally involves oral corticosteroids, followed by corticosteroid-sparing regimens.

Subacute cutaneous lupus erythematosus is a chronic autoimmune disease that predominantly affects younger women. Common findings in SCLE include red scaly plaques and ring-shaped lesions on sun-exposed areas of the skin.¹⁴ Subacute cutaneous lupus erythematosus primarily is characterized by a photosensitive rash, often with arthralgia, myalgia, and/or oral ulcers; less commonly, a small percentage of patients can experience central nervous system involvement, vasculitis, or nephritis. The histologic findings of SCLE include hydropic degeneration of the basal cell layer and periadnexal infiltrates (Figure 5). The incidence of SCLE often is associated with anti-Ro (SSA) and anti-La (SSB) antibodies.¹⁵ Treatment of SCLE focuses on managing skin symptoms with corticosteroids, antimalarials, and sun protection.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

The Diagnosis: Glomangiomyoma

The nail unit excision specimen showed collections of cuboidal cells and spindled cells within the corium that were consistent with a diagnosis of a glomangiomyoma, a rare glomus tumor variant (Figure). Glomus tumors are benign neoplasms comprising glomus bodies, which are arteriovenous anastomoses involved in thermoregulation.¹ They develop in areas densely populated by glomus bodies, including the fingers, toes, and subungual areas. Glomus tumors most commonly develop in middle-aged women.² Clinically, they manifest with a characteristic triad of intense pain, point tenderness, and cold sensitivity and may appear as reddish-pink or blue macules under the nail plate and/or longitudinal erythronychia.^2-6 The presence of multiple glomus tumors is associated with neurofibromatosis type 1.⁷ 

Advanced imaging including ultrasonography and magnetic resonance imaging (MRI) may help confirm the diagnosis but may not be cost effective, as excision with histopathology is needed to relieve symptoms and render a definitive diagnosis. Radiography is highly insensitive in identifying bone erosions associated with glomus tumors.⁸ With ultrasonography, glomus tumors appear hypoechoic; with Doppler ultrasonography, they appear hypervascular. With MRI, glomus tumors appear as well-defined nodular lesions with hypointense signal intensity on T1-weighted sequence and hyperintense signal intensity on T2-weighted sequence, with strong enhancement using gadolinium-based contrast.^9,10 On histopathology, a glomus tumor appears as a nodular tumor with sheets of oval-nucleated cells arranged in multicellular layers surrounding blood vessels and are immunoreactive for α-smooth muscle actin, muscle-specific actin, and type IV collagen.^11,12 

There are several glomus tumor variants. The most common is a solid glomus tumor, which predominantly is composed of glomus cells, followed by glomangioma, which mainly is composed of blood vessels. Glomangiomyoma, which mostly is composed of smooth muscle cells, is the rarest variant.¹³ 

While glomus tumors are common in the subungual areas, it is an uncommon location for glomangiomyomas, which have been reported in the nail unit in only 7 prior case reports identified through searches of PubMed and Google Scholar using the terms glomangiomyoma, glomangiomyoma nail, and subungual glomangiomyoma (Table).^13-19 Glomangiomyomas more commonly are described in solid organs, including the stomach, kidney, pancreas, and bladder.¹⁶ The mean age of patients with subungual glomangiomyomas, including our patient, was 40.4 years (range, 3-61 years), with the majority being female (75.0% [6/8]). Most patients presented with fingernail involvement (75.0% [6/8]), nail dystrophy (eg, nail plate thinning, longitudinal grooves, splinter hemorrhages, longitudinal erythronychia)(62.5% [5/8]), and intermittent pain and/or point tenderness in the affected nail (75.0% [6/8]).^13-19 Notably, only our patient had longitudinal erythronychia as a clinical feature, and only one other case described MRI findings, which included a lobulated mass with intense contrast and distal phalanx destruction.¹⁸ One patient was a 3-year-old girl with a family history of generalized multiple glomangiomyomas. Although subungual glomangiomyoma was not confirmed on histopathology, the diagnosis in this patient was presumed based on her family history.¹³ On histopathology, glomangiomyomas are composed of oval-nucleated cells surrounding blood vessels. These oval-nucleated cells then gradually transition to smooth muscle cells.²⁰ 

A myxoid cyst is composed of a pseudocyst, which lacks a cyst lining, and is a result of synovial fluid from the distal interphalangeal joint entering the pseudocyst space.² It typically manifests with a longitudinal groove in the nail plate. A flesh-colored nodule may be appreciated between the cuticle and the distal interphalangeal joint.² The depth of the longitudinal groove may vary depending on the volume of synovial fluid within the myxoid cyst.²¹ In a series of 35 cases of subungual myxoid cysts, none manifested with longitudinal erythronychia. Due to their composition, myxoid cysts can be distinguished easily from solid tumors of the nail unit via transillumination.²² Pain is a much less common with myxoid cysts vs glomus tumors, as the filling of the pseudocyst space with synovial fluid typically is gradual, allowing the surrounding tissue to accommodate and adapt over time.²¹ In equivocal cases, MRI or high-resolution ultrasonography may be used to distinguish myxoid cysts and glomus tumors.⁸ Histopathology shows accumulation of mucin in the dermis with surrounding fibrous stroma.²³

Subungual neuromas are painful benign tumors that develop due to disorganized neural proliferation following disruption to peripheral nerves secondary to trauma or surgery. In 3 case reports, subungual neuromas manifested as painful subungual nodules, with proximal nail plate ridging, or onycholysis.^24-26 Since neuromas have only rarely been described in the subungual region, reports of MRI and ultrasonography findings are unknown. Histopathology is needed to distinguish neuromas from glomus tumors. Histopathology shows an acapsular structure consisting of disorganized spindle-cell proliferation and nerve fibers arranged in a tangle of fascicles within fibrotic tissue.²⁵ On immunochemistry, spindle cells typically are positive for cellular antigen protein S100.²⁶ 

Leiomyomas are benign neoplasms derived from smooth muscle, typically localized to the uterus or gastrointestinal tract, and have been described rarely in the nail unit.^27,28 It is hypothesized that subungual leiomyomas originate from the vascular smooth muscle in the subcutaneous layer of the nail unit.²⁸ Like glomus tumors, leiomyomas of the subungual region often manifest with pain and longitudinal erythronychia.^27-30 Subungual leiomyomas may be distinguished from glomus tumors via advanced imaging techniques, including ultrasonography and MRI. Cutaneous leiomyomas have been described with mild to moderate internal low flow vascularity on Doppler ultrasonography, while glomus tumors typically reveal high internal vascularity.²⁸ Biopsy with histopathology is needed for definitive diagnosis. On histopathology, leiomyomas demonstrate bland-appearing spindle-shaped cells with elongated nuclei arranged in fascicles.²⁷ They typically are positive for α-smooth muscle actin and caldesmon on immunostaining. 

Eccrine spiradenomas are benign adnexal tumors likely of apocrine origin with limited case reports in the literature.^31,32 Clinically, eccrine spiradenomas involving the nail unit may manifest with longitudinal nail splitting of the nail or as a papule on the proximal nail fold, with associated tenderness.^31,32 In a report of a 50-year-old woman with a histopathologically confirmed eccrine spiradenoma manifesting with longitudinal splitting of the nail and pain in the proximal nail fold, the mass appeared hypoechoic on ultrasonography with increased intramass vascularity on Doppler, while MRI showed an intensely enhancing lesion.³¹ These imaging features, combined with a classically manifesting feature of pain, make eccrine spiradenomas difficult to distinguish from glomus tumors; therefore, histopathologic examination can provide a definitive diagnosis, and surgical excision is used for treatment.³¹ On histopathology, these tumors are well circumscribed and composed of both small dark basaloid cells with peripheral compact nuclei and larger cells with central pale nuclei, which may be arranged in tubules.^31,32

The Diagnosis: Glomangiomyoma

The nail unit excision specimen showed collections of cuboidal cells and spindled cells within the corium that were consistent with a diagnosis of a glomangiomyoma, a rare glomus tumor variant (Figure). Glomus tumors are benign neoplasms comprising glomus bodies, which are arteriovenous anastomoses involved in thermoregulation.¹ They develop in areas densely populated by glomus bodies, including the fingers, toes, and subungual areas. Glomus tumors most commonly develop in middle-aged women.² Clinically, they manifest with a characteristic triad of intense pain, point tenderness, and cold sensitivity and may appear as reddish-pink or blue macules under the nail plate and/or longitudinal erythronychia.^2-6 The presence of multiple glomus tumors is associated with neurofibromatosis type 1.⁷ 

Advanced imaging including ultrasonography and magnetic resonance imaging (MRI) may help confirm the diagnosis but may not be cost effective, as excision with histopathology is needed to relieve symptoms and render a definitive diagnosis. Radiography is highly insensitive in identifying bone erosions associated with glomus tumors.⁸ With ultrasonography, glomus tumors appear hypoechoic; with Doppler ultrasonography, they appear hypervascular. With MRI, glomus tumors appear as well-defined nodular lesions with hypointense signal intensity on T1-weighted sequence and hyperintense signal intensity on T2-weighted sequence, with strong enhancement using gadolinium-based contrast.^9,10 On histopathology, a glomus tumor appears as a nodular tumor with sheets of oval-nucleated cells arranged in multicellular layers surrounding blood vessels and are immunoreactive for α-smooth muscle actin, muscle-specific actin, and type IV collagen.^11,12 

There are several glomus tumor variants. The most common is a solid glomus tumor, which predominantly is composed of glomus cells, followed by glomangioma, which mainly is composed of blood vessels. Glomangiomyoma, which mostly is composed of smooth muscle cells, is the rarest variant.¹³ 

While glomus tumors are common in the subungual areas, it is an uncommon location for glomangiomyomas, which have been reported in the nail unit in only 7 prior case reports identified through searches of PubMed and Google Scholar using the terms glomangiomyoma, glomangiomyoma nail, and subungual glomangiomyoma (Table).^13-19 Glomangiomyomas more commonly are described in solid organs, including the stomach, kidney, pancreas, and bladder.¹⁶ The mean age of patients with subungual glomangiomyomas, including our patient, was 40.4 years (range, 3-61 years), with the majority being female (75.0% [6/8]). Most patients presented with fingernail involvement (75.0% [6/8]), nail dystrophy (eg, nail plate thinning, longitudinal grooves, splinter hemorrhages, longitudinal erythronychia)(62.5% [5/8]), and intermittent pain and/or point tenderness in the affected nail (75.0% [6/8]).^13-19 Notably, only our patient had longitudinal erythronychia as a clinical feature, and only one other case described MRI findings, which included a lobulated mass with intense contrast and distal phalanx destruction.¹⁸ One patient was a 3-year-old girl with a family history of generalized multiple glomangiomyomas. Although subungual glomangiomyoma was not confirmed on histopathology, the diagnosis in this patient was presumed based on her family history.¹³ On histopathology, glomangiomyomas are composed of oval-nucleated cells surrounding blood vessels. These oval-nucleated cells then gradually transition to smooth muscle cells.²⁰ 

A myxoid cyst is composed of a pseudocyst, which lacks a cyst lining, and is a result of synovial fluid from the distal interphalangeal joint entering the pseudocyst space.² It typically manifests with a longitudinal groove in the nail plate. A flesh-colored nodule may be appreciated between the cuticle and the distal interphalangeal joint.² The depth of the longitudinal groove may vary depending on the volume of synovial fluid within the myxoid cyst.²¹ In a series of 35 cases of subungual myxoid cysts, none manifested with longitudinal erythronychia. Due to their composition, myxoid cysts can be distinguished easily from solid tumors of the nail unit via transillumination.²² Pain is a much less common with myxoid cysts vs glomus tumors, as the filling of the pseudocyst space with synovial fluid typically is gradual, allowing the surrounding tissue to accommodate and adapt over time.²¹ In equivocal cases, MRI or high-resolution ultrasonography may be used to distinguish myxoid cysts and glomus tumors.⁸ Histopathology shows accumulation of mucin in the dermis with surrounding fibrous stroma.²³

Subungual neuromas are painful benign tumors that develop due to disorganized neural proliferation following disruption to peripheral nerves secondary to trauma or surgery. In 3 case reports, subungual neuromas manifested as painful subungual nodules, with proximal nail plate ridging, or onycholysis.^24-26 Since neuromas have only rarely been described in the subungual region, reports of MRI and ultrasonography findings are unknown. Histopathology is needed to distinguish neuromas from glomus tumors. Histopathology shows an acapsular structure consisting of disorganized spindle-cell proliferation and nerve fibers arranged in a tangle of fascicles within fibrotic tissue.²⁵ On immunochemistry, spindle cells typically are positive for cellular antigen protein S100.²⁶ 

Leiomyomas are benign neoplasms derived from smooth muscle, typically localized to the uterus or gastrointestinal tract, and have been described rarely in the nail unit.^27,28 It is hypothesized that subungual leiomyomas originate from the vascular smooth muscle in the subcutaneous layer of the nail unit.²⁸ Like glomus tumors, leiomyomas of the subungual region often manifest with pain and longitudinal erythronychia.^27-30 Subungual leiomyomas may be distinguished from glomus tumors via advanced imaging techniques, including ultrasonography and MRI. Cutaneous leiomyomas have been described with mild to moderate internal low flow vascularity on Doppler ultrasonography, while glomus tumors typically reveal high internal vascularity.²⁸ Biopsy with histopathology is needed for definitive diagnosis. On histopathology, leiomyomas demonstrate bland-appearing spindle-shaped cells with elongated nuclei arranged in fascicles.²⁷ They typically are positive for α-smooth muscle actin and caldesmon on immunostaining. 

Eccrine spiradenomas are benign adnexal tumors likely of apocrine origin with limited case reports in the literature.^31,32 Clinically, eccrine spiradenomas involving the nail unit may manifest with longitudinal nail splitting of the nail or as a papule on the proximal nail fold, with associated tenderness.^31,32 In a report of a 50-year-old woman with a histopathologically confirmed eccrine spiradenoma manifesting with longitudinal splitting of the nail and pain in the proximal nail fold, the mass appeared hypoechoic on ultrasonography with increased intramass vascularity on Doppler, while MRI showed an intensely enhancing lesion.³¹ These imaging features, combined with a classically manifesting feature of pain, make eccrine spiradenomas difficult to distinguish from glomus tumors; therefore, histopathologic examination can provide a definitive diagnosis, and surgical excision is used for treatment.³¹ On histopathology, these tumors are well circumscribed and composed of both small dark basaloid cells with peripheral compact nuclei and larger cells with central pale nuclei, which may be arranged in tubules.^31,32

The Diagnosis: Glomangiomyoma

The nail unit excision specimen showed collections of cuboidal cells and spindled cells within the corium that were consistent with a diagnosis of a glomangiomyoma, a rare glomus tumor variant (Figure). Glomus tumors are benign neoplasms comprising glomus bodies, which are arteriovenous anastomoses involved in thermoregulation.¹ They develop in areas densely populated by glomus bodies, including the fingers, toes, and subungual areas. Glomus tumors most commonly develop in middle-aged women.² Clinically, they manifest with a characteristic triad of intense pain, point tenderness, and cold sensitivity and may appear as reddish-pink or blue macules under the nail plate and/or longitudinal erythronychia.^2-6 The presence of multiple glomus tumors is associated with neurofibromatosis type 1.⁷ 

Advanced imaging including ultrasonography and magnetic resonance imaging (MRI) may help confirm the diagnosis but may not be cost effective, as excision with histopathology is needed to relieve symptoms and render a definitive diagnosis. Radiography is highly insensitive in identifying bone erosions associated with glomus tumors.⁸ With ultrasonography, glomus tumors appear hypoechoic; with Doppler ultrasonography, they appear hypervascular. With MRI, glomus tumors appear as well-defined nodular lesions with hypointense signal intensity on T1-weighted sequence and hyperintense signal intensity on T2-weighted sequence, with strong enhancement using gadolinium-based contrast.^9,10 On histopathology, a glomus tumor appears as a nodular tumor with sheets of oval-nucleated cells arranged in multicellular layers surrounding blood vessels and are immunoreactive for α-smooth muscle actin, muscle-specific actin, and type IV collagen.^11,12 

There are several glomus tumor variants. The most common is a solid glomus tumor, which predominantly is composed of glomus cells, followed by glomangioma, which mainly is composed of blood vessels. Glomangiomyoma, which mostly is composed of smooth muscle cells, is the rarest variant.¹³ 

While glomus tumors are common in the subungual areas, it is an uncommon location for glomangiomyomas, which have been reported in the nail unit in only 7 prior case reports identified through searches of PubMed and Google Scholar using the terms glomangiomyoma, glomangiomyoma nail, and subungual glomangiomyoma (Table).^13-19 Glomangiomyomas more commonly are described in solid organs, including the stomach, kidney, pancreas, and bladder.¹⁶ The mean age of patients with subungual glomangiomyomas, including our patient, was 40.4 years (range, 3-61 years), with the majority being female (75.0% [6/8]). Most patients presented with fingernail involvement (75.0% [6/8]), nail dystrophy (eg, nail plate thinning, longitudinal grooves, splinter hemorrhages, longitudinal erythronychia)(62.5% [5/8]), and intermittent pain and/or point tenderness in the affected nail (75.0% [6/8]).^13-19 Notably, only our patient had longitudinal erythronychia as a clinical feature, and only one other case described MRI findings, which included a lobulated mass with intense contrast and distal phalanx destruction.¹⁸ One patient was a 3-year-old girl with a family history of generalized multiple glomangiomyomas. Although subungual glomangiomyoma was not confirmed on histopathology, the diagnosis in this patient was presumed based on her family history.¹³ On histopathology, glomangiomyomas are composed of oval-nucleated cells surrounding blood vessels. These oval-nucleated cells then gradually transition to smooth muscle cells.²⁰ 

A myxoid cyst is composed of a pseudocyst, which lacks a cyst lining, and is a result of synovial fluid from the distal interphalangeal joint entering the pseudocyst space.² It typically manifests with a longitudinal groove in the nail plate. A flesh-colored nodule may be appreciated between the cuticle and the distal interphalangeal joint.² The depth of the longitudinal groove may vary depending on the volume of synovial fluid within the myxoid cyst.²¹ In a series of 35 cases of subungual myxoid cysts, none manifested with longitudinal erythronychia. Due to their composition, myxoid cysts can be distinguished easily from solid tumors of the nail unit via transillumination.²² Pain is a much less common with myxoid cysts vs glomus tumors, as the filling of the pseudocyst space with synovial fluid typically is gradual, allowing the surrounding tissue to accommodate and adapt over time.²¹ In equivocal cases, MRI or high-resolution ultrasonography may be used to distinguish myxoid cysts and glomus tumors.⁸ Histopathology shows accumulation of mucin in the dermis with surrounding fibrous stroma.²³

Subungual neuromas are painful benign tumors that develop due to disorganized neural proliferation following disruption to peripheral nerves secondary to trauma or surgery. In 3 case reports, subungual neuromas manifested as painful subungual nodules, with proximal nail plate ridging, or onycholysis.^24-26 Since neuromas have only rarely been described in the subungual region, reports of MRI and ultrasonography findings are unknown. Histopathology is needed to distinguish neuromas from glomus tumors. Histopathology shows an acapsular structure consisting of disorganized spindle-cell proliferation and nerve fibers arranged in a tangle of fascicles within fibrotic tissue.²⁵ On immunochemistry, spindle cells typically are positive for cellular antigen protein S100.²⁶ 

Leiomyomas are benign neoplasms derived from smooth muscle, typically localized to the uterus or gastrointestinal tract, and have been described rarely in the nail unit.^27,28 It is hypothesized that subungual leiomyomas originate from the vascular smooth muscle in the subcutaneous layer of the nail unit.²⁸ Like glomus tumors, leiomyomas of the subungual region often manifest with pain and longitudinal erythronychia.^27-30 Subungual leiomyomas may be distinguished from glomus tumors via advanced imaging techniques, including ultrasonography and MRI. Cutaneous leiomyomas have been described with mild to moderate internal low flow vascularity on Doppler ultrasonography, while glomus tumors typically reveal high internal vascularity.²⁸ Biopsy with histopathology is needed for definitive diagnosis. On histopathology, leiomyomas demonstrate bland-appearing spindle-shaped cells with elongated nuclei arranged in fascicles.²⁷ They typically are positive for α-smooth muscle actin and caldesmon on immunostaining. 

Eccrine spiradenomas are benign adnexal tumors likely of apocrine origin with limited case reports in the literature.^31,32 Clinically, eccrine spiradenomas involving the nail unit may manifest with longitudinal nail splitting of the nail or as a papule on the proximal nail fold, with associated tenderness.^31,32 In a report of a 50-year-old woman with a histopathologically confirmed eccrine spiradenoma manifesting with longitudinal splitting of the nail and pain in the proximal nail fold, the mass appeared hypoechoic on ultrasonography with increased intramass vascularity on Doppler, while MRI showed an intensely enhancing lesion.³¹ These imaging features, combined with a classically manifesting feature of pain, make eccrine spiradenomas difficult to distinguish from glomus tumors; therefore, histopathologic examination can provide a definitive diagnosis, and surgical excision is used for treatment.³¹ On histopathology, these tumors are well circumscribed and composed of both small dark basaloid cells with peripheral compact nuclei and larger cells with central pale nuclei, which may be arranged in tubules.^31,32

To the Editor:

Necrobiotic xanthogranuloma (NXG) is classified as a cutaneous non–Langerhans cell histiocytosis, often seen with monoclonal gammopathy of undetermined significance or multiple myeloma.¹ Clinically, it appears as a red or yellow plaque with occasional ulceration and telangiectasias, most commonly seen periorbitally and on the trunk. On pathology, NXG appears as necrobiosis, giant cells, and various inflammatory cells extending into the subcutaneous tissue.² In this article, we describe a rare presentation of NXG in location and skin type.

A 52-year-old woman with a history of systemic lupus erythematosus (SLE) presented with alopecia and a tender lesion on the scalp of 5 years’ duration (Figure 1). The patient had no history of a similar lesion, and no other lesions were present. A biopsy performed at an outside clinic a few weeks to months prior to the initial presentation to our clinic showed NXG (Figure 2). Evaluation at our clinic revealed a 4x4-cm orange-brown annular plaque on the left parietal scalp. Serum and urine protein electrophoresis studies were negative. The patient reported she was up to date with recommended screenings such as mammography and colonoscopy. 

We started the patient on topical triamcinolone and topical ruxolitinib and administered intralesional triamcinolone. She was already taking hydroxychloroquine and leflunomide for SLE. Three weeks later, she returned with improved symptoms and appearance (Figure 1). She remained on intralesional triamcinolone and ruxolitinib and continues to experience improvement.

Necrobiotic xanthogranuloma is rare and typically is associated with monoclonal gammopathy.² In one study, 83 of 100 of patients with NXG presented with or were found to have a monoclonal gammopathy.² In another study, paraproteinemia was detected in 82.1% of patients.³ The majority of case reports and systematic reviews detail periorbital or thoracic lesions.⁴ The location on the scalp and lack of association with paraproteinemia make this a rare presentation of NXG. Studies may be warranted to explore any association of SLE with NXG if more cases present.

In a multicenter cross-sectional study and systematic review of 235 patients with NXG, 87% were White, 12% were Asian, and only 1% were Black or African American.³ The limited representation of skin of color raises concern for the possibility of missed diagnoses and delays in care. 

Treatment of NXG often is multimodal with use of intravenous immunoglobulin, oral steroids, chlorambucil, melphalan, and other alkylating agents, and response is variable.^3-6 Recent studies show treatment effectiveness with Janus kinase inhibitors in granulomatous dermatitides.^7-9 As our patient was not responding to prior treatments, we decided to try ruxolitinib, and she has continued to improve with it.^10,11 Interestingly, the patient experienced continued improvement with intralesional triamcinolone, which is not often reported in the literature.^2-6 Overall, NXG is an extremely rare condition that requires special care in workup to rule out paraproteinemia and a thoughtful approach to treatment modalities.

To the Editor:

Necrobiotic xanthogranuloma (NXG) is classified as a cutaneous non–Langerhans cell histiocytosis, often seen with monoclonal gammopathy of undetermined significance or multiple myeloma.¹ Clinically, it appears as a red or yellow plaque with occasional ulceration and telangiectasias, most commonly seen periorbitally and on the trunk. On pathology, NXG appears as necrobiosis, giant cells, and various inflammatory cells extending into the subcutaneous tissue.² In this article, we describe a rare presentation of NXG in location and skin type.

A 52-year-old woman with a history of systemic lupus erythematosus (SLE) presented with alopecia and a tender lesion on the scalp of 5 years’ duration (Figure 1). The patient had no history of a similar lesion, and no other lesions were present. A biopsy performed at an outside clinic a few weeks to months prior to the initial presentation to our clinic showed NXG (Figure 2). Evaluation at our clinic revealed a 4x4-cm orange-brown annular plaque on the left parietal scalp. Serum and urine protein electrophoresis studies were negative. The patient reported she was up to date with recommended screenings such as mammography and colonoscopy. 

We started the patient on topical triamcinolone and topical ruxolitinib and administered intralesional triamcinolone. She was already taking hydroxychloroquine and leflunomide for SLE. Three weeks later, she returned with improved symptoms and appearance (Figure 1). She remained on intralesional triamcinolone and ruxolitinib and continues to experience improvement.

Necrobiotic xanthogranuloma is rare and typically is associated with monoclonal gammopathy.² In one study, 83 of 100 of patients with NXG presented with or were found to have a monoclonal gammopathy.² In another study, paraproteinemia was detected in 82.1% of patients.³ The majority of case reports and systematic reviews detail periorbital or thoracic lesions.⁴ The location on the scalp and lack of association with paraproteinemia make this a rare presentation of NXG. Studies may be warranted to explore any association of SLE with NXG if more cases present.

In a multicenter cross-sectional study and systematic review of 235 patients with NXG, 87% were White, 12% were Asian, and only 1% were Black or African American.³ The limited representation of skin of color raises concern for the possibility of missed diagnoses and delays in care. 

Treatment of NXG often is multimodal with use of intravenous immunoglobulin, oral steroids, chlorambucil, melphalan, and other alkylating agents, and response is variable.^3-6 Recent studies show treatment effectiveness with Janus kinase inhibitors in granulomatous dermatitides.^7-9 As our patient was not responding to prior treatments, we decided to try ruxolitinib, and she has continued to improve with it.^10,11 Interestingly, the patient experienced continued improvement with intralesional triamcinolone, which is not often reported in the literature.^2-6 Overall, NXG is an extremely rare condition that requires special care in workup to rule out paraproteinemia and a thoughtful approach to treatment modalities.

To the Editor:

Necrobiotic xanthogranuloma (NXG) is classified as a cutaneous non–Langerhans cell histiocytosis, often seen with monoclonal gammopathy of undetermined significance or multiple myeloma.¹ Clinically, it appears as a red or yellow plaque with occasional ulceration and telangiectasias, most commonly seen periorbitally and on the trunk. On pathology, NXG appears as necrobiosis, giant cells, and various inflammatory cells extending into the subcutaneous tissue.² In this article, we describe a rare presentation of NXG in location and skin type.

A 52-year-old woman with a history of systemic lupus erythematosus (SLE) presented with alopecia and a tender lesion on the scalp of 5 years’ duration (Figure 1). The patient had no history of a similar lesion, and no other lesions were present. A biopsy performed at an outside clinic a few weeks to months prior to the initial presentation to our clinic showed NXG (Figure 2). Evaluation at our clinic revealed a 4x4-cm orange-brown annular plaque on the left parietal scalp. Serum and urine protein electrophoresis studies were negative. The patient reported she was up to date with recommended screenings such as mammography and colonoscopy. 

We started the patient on topical triamcinolone and topical ruxolitinib and administered intralesional triamcinolone. She was already taking hydroxychloroquine and leflunomide for SLE. Three weeks later, she returned with improved symptoms and appearance (Figure 1). She remained on intralesional triamcinolone and ruxolitinib and continues to experience improvement.

Necrobiotic xanthogranuloma is rare and typically is associated with monoclonal gammopathy.² In one study, 83 of 100 of patients with NXG presented with or were found to have a monoclonal gammopathy.² In another study, paraproteinemia was detected in 82.1% of patients.³ The majority of case reports and systematic reviews detail periorbital or thoracic lesions.⁴ The location on the scalp and lack of association with paraproteinemia make this a rare presentation of NXG. Studies may be warranted to explore any association of SLE with NXG if more cases present.

In a multicenter cross-sectional study and systematic review of 235 patients with NXG, 87% were White, 12% were Asian, and only 1% were Black or African American.³ The limited representation of skin of color raises concern for the possibility of missed diagnoses and delays in care. 

Treatment of NXG often is multimodal with use of intravenous immunoglobulin, oral steroids, chlorambucil, melphalan, and other alkylating agents, and response is variable.^3-6 Recent studies show treatment effectiveness with Janus kinase inhibitors in granulomatous dermatitides.^7-9 As our patient was not responding to prior treatments, we decided to try ruxolitinib, and she has continued to improve with it.^10,11 Interestingly, the patient experienced continued improvement with intralesional triamcinolone, which is not often reported in the literature.^2-6 Overall, NXG is an extremely rare condition that requires special care in workup to rule out paraproteinemia and a thoughtful approach to treatment modalities.

As the health care landscape continues to shift, direct care (also known as direct pay) models have emerged as attractive alternatives to traditional insurance-based practice. For dermatology residents poised to enter the workforce, the direct care model offers potential advantages in autonomy, patient relationships, and work-life balance, but not without considerable risks and operational challenges. This article explores the key benefits and drawbacks of starting a direct care dermatology practice, providing a framework to help early-career dermatologists determine whether this path aligns with their personal and professional goals.

The transition from dermatology residency to clinical practice allows for a variety of paths, from large academic institutions to private practice to corporate entities (private equity–owned groups). In recent years, the direct care model has gained traction, particularly among physicians seeking greater autonomy and a more sustainable pace of practice.

Direct care dermatology practices operate outside the constraints of third-party payers, offering patients transparent pricing and direct access to care in exchange for fees paid out of pocket. By eliminating insurance companies as the middleman, it allows for less overhead, longer visits with patients, and increased access to care; however, though this model may seem appealing, direct care practices are not without their own set of challenges, especially amid rising concerns over physician burnout and administrative burden. 

This article explores the key benefits and drawbacks of starting a direct care dermatology practice, providing a framework to help early-career dermatologists determine whether this path aligns with their personal and professional goals.

The Case for Direct Care Dermatology

Autonomy and Control—Perhaps the most compelling advantage of the direct care model is clinical and operational autonomy. Without insurance contracts dictating codes, coverage limitations, and documentation demands, physicians regain full control over their practice—how much time they spend with each patient, what treatments they offer, and how they structure their schedules. This option is ideal for those who want to practice medicine the way they were trained—thoroughly, thoughtfully, and without rushing.

Improved Work-Life Balance—The direct care model allows for smaller patient panels, longer visits, and more flexible hours. In contrast to the high patient volumes required to maintain profitability in insurance-based models, direct care dermatologists often can sustain their practice with a smaller number of daily appointments. This results in reduced administrative overhead and the potential for substantial reduction in burnout, a concern that has been well documented among dermatologists in high-volume settings.^1-3 As a result, physicians are less likely to rush through patient visits or be consumed by concerns of falling behind, ultimately causing them to question their career choice.

Closer Patient Relationships—With fewer patients and longer visits, dermatologists often find the direct care model fosters a stronger therapeutic alliance that can improve treatment adherence, outcomes, and overall patient satisfaction. Additionally, patients often appreciate transparent pricing, the ability to reach their dermatologist more directly, and a sense of being truly seen and heard. This, in turn, can make dermatology more rewarding for the provider.

Entrepreneurial Opportunity—Direct care offers entrepreneurial individuals the chance to build a brand and shape a niche. It also provides the flexibility to explore complementary or alternative practice models.

The Challenges of Going Direct

Despite its appeal, starting a direct care practice is not without substantial risks and hurdles—particularly for residents just out of training. These challenges include financial risks and startup costs, market uncertainty, lack of mentorship or support, and limitations in treating complex dermatologic conditions.

Financial Risk and Startup Costs—Launching any solo practice involves a considerable financial investment up front, including rent, medical equipment, electronic medical record systems, malpractice insurance, marketing, and staffing. In a direct care model, there is the added pressure of building a patient base without the referral stream of insurance contracts. In the first 6 to 12 months, income may be minimal, making this route challenging without savings, a financial cushion, or external funding.

Market Uncertainty—The success of direct care dermatology depends heavily on local market dynamics. In affluent or health-literate communities, patients may be more willing to pay out of pocket for expedited or personalized care; however, in other areas, patients may be unwilling or unable to do so—especially if they are accustomed to using insurance. Physicians may find that some of their patients will choose to see a different dermatologist for certain procedures because it is covered by their insurance.

Lack of Immediate Mentorship or Support—Transitioning from residency to independent practice (in any model) can be difficult. Residency provides a structured, team-based environment with colleagues and mentors at every turn. A solo or small-group direct care practice may feel isolating, especially in the early months. Without senior physicians to consult with on challenging cases or administrative decisions, the learning curve can be steep. Early-career dermatologists must be confident in their clinical acumen and be prepared to seek out alternative mentorship or continuing education opportunities.

Limitations in Complex Medical Dermatology—While direct care excels in most general dermatology visit types (from medical and cosmetic to minor surgical), this model may be less suited for patients requiring complex care coordination. Patients with high-cost conditions such as immunobullous diseases or those needing systemic immunosuppressives may still require referral to academic centers or insurance-covered specialists. Additionally, costlier procedures such as Mohs micrographic surgery may not fit well into a direct pay model, which may limit the scope of practice for direct care dermatologists in this subspecialty.

Considerations for Residents

Before committing to practicing via a direct care model, dermatology residents should reflect on the following:

• Risk tolerance: Are you comfortable navigating the business and financial risk?
• Location: Does your target community have patients willing and able to pay out of pocket?
• Scope of interest: Will a direct care practice align with your clinical passions?
• Support systems: Do you have access to mentors, legal and financial advisors, and operational support?
• Long-term goals: Are you building a lifestyle practice, a scalable business, or a stepping stone to a future opportunity?

Ultimately, the decision to pursue a direct care model requires careful reflection on personal values, financial preparedness, and the unique needs of the community one intends to serve.

Final Thoughts

The direct care dermatology model offers an appealing alternative to traditional practice, especially for those prioritizing autonomy, patient connection, and work-life balance; however, it demands an entrepreneurial spirit as well as careful planning and an acceptance of financial uncertainty—factors that may pose challenges for new graduates. For dermatology residents, the decision to pursue direct care should be grounded in personal values, practical considerations, and a clear understanding of both the opportunities and limitations of this evolving practice model.

As the health care landscape continues to shift, direct care (also known as direct pay) models have emerged as attractive alternatives to traditional insurance-based practice. For dermatology residents poised to enter the workforce, the direct care model offers potential advantages in autonomy, patient relationships, and work-life balance, but not without considerable risks and operational challenges. This article explores the key benefits and drawbacks of starting a direct care dermatology practice, providing a framework to help early-career dermatologists determine whether this path aligns with their personal and professional goals.

The transition from dermatology residency to clinical practice allows for a variety of paths, from large academic institutions to private practice to corporate entities (private equity–owned groups). In recent years, the direct care model has gained traction, particularly among physicians seeking greater autonomy and a more sustainable pace of practice.

Direct care dermatology practices operate outside the constraints of third-party payers, offering patients transparent pricing and direct access to care in exchange for fees paid out of pocket. By eliminating insurance companies as the middleman, it allows for less overhead, longer visits with patients, and increased access to care; however, though this model may seem appealing, direct care practices are not without their own set of challenges, especially amid rising concerns over physician burnout and administrative burden. 

This article explores the key benefits and drawbacks of starting a direct care dermatology practice, providing a framework to help early-career dermatologists determine whether this path aligns with their personal and professional goals.

The Case for Direct Care Dermatology

Autonomy and Control—Perhaps the most compelling advantage of the direct care model is clinical and operational autonomy. Without insurance contracts dictating codes, coverage limitations, and documentation demands, physicians regain full control over their practice—how much time they spend with each patient, what treatments they offer, and how they structure their schedules. This option is ideal for those who want to practice medicine the way they were trained—thoroughly, thoughtfully, and without rushing.

Improved Work-Life Balance—The direct care model allows for smaller patient panels, longer visits, and more flexible hours. In contrast to the high patient volumes required to maintain profitability in insurance-based models, direct care dermatologists often can sustain their practice with a smaller number of daily appointments. This results in reduced administrative overhead and the potential for substantial reduction in burnout, a concern that has been well documented among dermatologists in high-volume settings.^1-3 As a result, physicians are less likely to rush through patient visits or be consumed by concerns of falling behind, ultimately causing them to question their career choice.

Closer Patient Relationships—With fewer patients and longer visits, dermatologists often find the direct care model fosters a stronger therapeutic alliance that can improve treatment adherence, outcomes, and overall patient satisfaction. Additionally, patients often appreciate transparent pricing, the ability to reach their dermatologist more directly, and a sense of being truly seen and heard. This, in turn, can make dermatology more rewarding for the provider.

Entrepreneurial Opportunity—Direct care offers entrepreneurial individuals the chance to build a brand and shape a niche. It also provides the flexibility to explore complementary or alternative practice models.

The Challenges of Going Direct

Despite its appeal, starting a direct care practice is not without substantial risks and hurdles—particularly for residents just out of training. These challenges include financial risks and startup costs, market uncertainty, lack of mentorship or support, and limitations in treating complex dermatologic conditions.

Financial Risk and Startup Costs—Launching any solo practice involves a considerable financial investment up front, including rent, medical equipment, electronic medical record systems, malpractice insurance, marketing, and staffing. In a direct care model, there is the added pressure of building a patient base without the referral stream of insurance contracts. In the first 6 to 12 months, income may be minimal, making this route challenging without savings, a financial cushion, or external funding.

Market Uncertainty—The success of direct care dermatology depends heavily on local market dynamics. In affluent or health-literate communities, patients may be more willing to pay out of pocket for expedited or personalized care; however, in other areas, patients may be unwilling or unable to do so—especially if they are accustomed to using insurance. Physicians may find that some of their patients will choose to see a different dermatologist for certain procedures because it is covered by their insurance.

Lack of Immediate Mentorship or Support—Transitioning from residency to independent practice (in any model) can be difficult. Residency provides a structured, team-based environment with colleagues and mentors at every turn. A solo or small-group direct care practice may feel isolating, especially in the early months. Without senior physicians to consult with on challenging cases or administrative decisions, the learning curve can be steep. Early-career dermatologists must be confident in their clinical acumen and be prepared to seek out alternative mentorship or continuing education opportunities.

Limitations in Complex Medical Dermatology—While direct care excels in most general dermatology visit types (from medical and cosmetic to minor surgical), this model may be less suited for patients requiring complex care coordination. Patients with high-cost conditions such as immunobullous diseases or those needing systemic immunosuppressives may still require referral to academic centers or insurance-covered specialists. Additionally, costlier procedures such as Mohs micrographic surgery may not fit well into a direct pay model, which may limit the scope of practice for direct care dermatologists in this subspecialty.

Considerations for Residents

Before committing to practicing via a direct care model, dermatology residents should reflect on the following:

• Risk tolerance: Are you comfortable navigating the business and financial risk?
• Location: Does your target community have patients willing and able to pay out of pocket?
• Scope of interest: Will a direct care practice align with your clinical passions?
• Support systems: Do you have access to mentors, legal and financial advisors, and operational support?
• Long-term goals: Are you building a lifestyle practice, a scalable business, or a stepping stone to a future opportunity?

Ultimately, the decision to pursue a direct care model requires careful reflection on personal values, financial preparedness, and the unique needs of the community one intends to serve.

Final Thoughts

The direct care dermatology model offers an appealing alternative to traditional practice, especially for those prioritizing autonomy, patient connection, and work-life balance; however, it demands an entrepreneurial spirit as well as careful planning and an acceptance of financial uncertainty—factors that may pose challenges for new graduates. For dermatology residents, the decision to pursue direct care should be grounded in personal values, practical considerations, and a clear understanding of both the opportunities and limitations of this evolving practice model.

As the health care landscape continues to shift, direct care (also known as direct pay) models have emerged as attractive alternatives to traditional insurance-based practice. For dermatology residents poised to enter the workforce, the direct care model offers potential advantages in autonomy, patient relationships, and work-life balance, but not without considerable risks and operational challenges. This article explores the key benefits and drawbacks of starting a direct care dermatology practice, providing a framework to help early-career dermatologists determine whether this path aligns with their personal and professional goals.

The transition from dermatology residency to clinical practice allows for a variety of paths, from large academic institutions to private practice to corporate entities (private equity–owned groups). In recent years, the direct care model has gained traction, particularly among physicians seeking greater autonomy and a more sustainable pace of practice.

Direct care dermatology practices operate outside the constraints of third-party payers, offering patients transparent pricing and direct access to care in exchange for fees paid out of pocket. By eliminating insurance companies as the middleman, it allows for less overhead, longer visits with patients, and increased access to care; however, though this model may seem appealing, direct care practices are not without their own set of challenges, especially amid rising concerns over physician burnout and administrative burden. 

This article explores the key benefits and drawbacks of starting a direct care dermatology practice, providing a framework to help early-career dermatologists determine whether this path aligns with their personal and professional goals.

The Case for Direct Care Dermatology

Autonomy and Control—Perhaps the most compelling advantage of the direct care model is clinical and operational autonomy. Without insurance contracts dictating codes, coverage limitations, and documentation demands, physicians regain full control over their practice—how much time they spend with each patient, what treatments they offer, and how they structure their schedules. This option is ideal for those who want to practice medicine the way they were trained—thoroughly, thoughtfully, and without rushing.

Improved Work-Life Balance—The direct care model allows for smaller patient panels, longer visits, and more flexible hours. In contrast to the high patient volumes required to maintain profitability in insurance-based models, direct care dermatologists often can sustain their practice with a smaller number of daily appointments. This results in reduced administrative overhead and the potential for substantial reduction in burnout, a concern that has been well documented among dermatologists in high-volume settings.^1-3 As a result, physicians are less likely to rush through patient visits or be consumed by concerns of falling behind, ultimately causing them to question their career choice.

Closer Patient Relationships—With fewer patients and longer visits, dermatologists often find the direct care model fosters a stronger therapeutic alliance that can improve treatment adherence, outcomes, and overall patient satisfaction. Additionally, patients often appreciate transparent pricing, the ability to reach their dermatologist more directly, and a sense of being truly seen and heard. This, in turn, can make dermatology more rewarding for the provider.

Entrepreneurial Opportunity—Direct care offers entrepreneurial individuals the chance to build a brand and shape a niche. It also provides the flexibility to explore complementary or alternative practice models.

The Challenges of Going Direct

Despite its appeal, starting a direct care practice is not without substantial risks and hurdles—particularly for residents just out of training. These challenges include financial risks and startup costs, market uncertainty, lack of mentorship or support, and limitations in treating complex dermatologic conditions.

Financial Risk and Startup Costs—Launching any solo practice involves a considerable financial investment up front, including rent, medical equipment, electronic medical record systems, malpractice insurance, marketing, and staffing. In a direct care model, there is the added pressure of building a patient base without the referral stream of insurance contracts. In the first 6 to 12 months, income may be minimal, making this route challenging without savings, a financial cushion, or external funding.

Market Uncertainty—The success of direct care dermatology depends heavily on local market dynamics. In affluent or health-literate communities, patients may be more willing to pay out of pocket for expedited or personalized care; however, in other areas, patients may be unwilling or unable to do so—especially if they are accustomed to using insurance. Physicians may find that some of their patients will choose to see a different dermatologist for certain procedures because it is covered by their insurance.

Lack of Immediate Mentorship or Support—Transitioning from residency to independent practice (in any model) can be difficult. Residency provides a structured, team-based environment with colleagues and mentors at every turn. A solo or small-group direct care practice may feel isolating, especially in the early months. Without senior physicians to consult with on challenging cases or administrative decisions, the learning curve can be steep. Early-career dermatologists must be confident in their clinical acumen and be prepared to seek out alternative mentorship or continuing education opportunities.

Limitations in Complex Medical Dermatology—While direct care excels in most general dermatology visit types (from medical and cosmetic to minor surgical), this model may be less suited for patients requiring complex care coordination. Patients with high-cost conditions such as immunobullous diseases or those needing systemic immunosuppressives may still require referral to academic centers or insurance-covered specialists. Additionally, costlier procedures such as Mohs micrographic surgery may not fit well into a direct pay model, which may limit the scope of practice for direct care dermatologists in this subspecialty.

Considerations for Residents

Before committing to practicing via a direct care model, dermatology residents should reflect on the following:

• Risk tolerance: Are you comfortable navigating the business and financial risk?
• Location: Does your target community have patients willing and able to pay out of pocket?
• Scope of interest: Will a direct care practice align with your clinical passions?
• Support systems: Do you have access to mentors, legal and financial advisors, and operational support?
• Long-term goals: Are you building a lifestyle practice, a scalable business, or a stepping stone to a future opportunity?

Ultimately, the decision to pursue a direct care model requires careful reflection on personal values, financial preparedness, and the unique needs of the community one intends to serve.

Final Thoughts

The direct care dermatology model offers an appealing alternative to traditional practice, especially for those prioritizing autonomy, patient connection, and work-life balance; however, it demands an entrepreneurial spirit as well as careful planning and an acceptance of financial uncertainty—factors that may pose challenges for new graduates. For dermatology residents, the decision to pursue direct care should be grounded in personal values, practical considerations, and a clear understanding of both the opportunities and limitations of this evolving practice model.

Steatocystomas are small sebum-filled cysts that typically manifest in the dermis and originate from sebaceous follicles. Although commonly asymptomatic, these lesions can manifest with pruritus or become infected, predisposing patients to further complications.¹ Steatocystomas can manifest as single (steatocystoma simplex [SS]) or numerous (steatocystoma multiplex [SM]) lesions; the lesions also can spontaneously rupture with characteristics that resemble hidradenitis suppurativa (HS)(steatocystoma multiplex suppurativa [SMS]).^1,2

Steatocystomas are relatively rare, and there is limited consensus in the published literature on the etiology and management of this condition. In this article, we present a comprehensive review of steatocystomas in the current literature. We highlight important features to consider when making the diagnosis and also offer recommendations for best-practice treatment.

Historical Background

Although not explicitly identified by name, the first documentation of steatocystomas is a case report published in 1873. In this account, the author described a patient who presented with approximately 250 flesh-colored dermal cysts across the body that varied in size.³ In 1899, the term steatocystoma multiple—derived from Greek roots meaning “fatty bag”—was first used.⁴

In 1982, almost a century later, Brownstein⁵ reported some of the earliest cases of SS. This solitary subtype is identical to SM on a microscopic level; however, unlike SM, this variant occurs as a single lesion that typically forms in adulthood and in the absence of family history. Other benign adnexal tumors (eg, pilomatricomas, pilar cysts, and sebaceous hyperplasias) also can manifest as either solitary or multiple lesions.

In 1976, McDonald and Reed⁶ reported the first known cases of patients with both SM and HS. At the time, the co-occurrence of these conditions was viewed as coincidental, but there were postulations of a shared inflammatory process and hereditary link⁶; it was not until 1982 that the term steatocystoma multiplex suppurativum was coined to describe this variant.⁷ Although rare, there have been multiple documented instances of SMS since. It has been suggested that the convergence of these conditions may indicate a shared follicular proliferation defect.⁸ Ongoing investigation is warranted to explain the underlying pathogenesis of this unique variant.

Epidemiology

The available epidemiologic data primarily relate to SM, the most common steatocystoma variant. Nevertheless, SM is a relatively rare condition, and the exact incidence and prevalence remain unknown.^8,9 Steatocystomas typically manifest in the first and second decades of life and have been observed in patients of both sexes, with studies demonstrating no notable sex bias.^4,9

Etiology and Pathophysiology

Steatocystomas can occur sporadically or may be inherited as an autosomal-dominant condition.⁴ Typically, SS tends to manifest as an isolated occurrence without any inherent genetic predisposition.⁵ Alternatively, SM may develop sporadically or be associated with a mutation in the keratin 17 gene (KRT17).⁴ Steatocystoma multiplex also has been associated with at least 4 different missense mutations, including N92H, R94H, and R94C, located on the long (q) arm of chromosome 17.^4,10-12

The keratin 17 gene is responsible for encoding the keratin 17 protein, a type I intermediate filament predominantly synthesized in the basal cells of epithelial tissue. This fibrous structural protein can regulate many processes, including inflammation and cell proliferation, and is found in regions such as the sebaceous glands, hair follicles, and eccrine sweat glands. Overexpression of KRT17 has been suggested in other cutaneous conditions, most notably psoriasis.¹² Despite KRT17’s many roles, it remains unclear why SM typically manifests with a myriad of sebum-containing cysts as the primary symptom.¹² Continued investigation into the genetic underpinnings of SM and the keratin 17 protein is necessary to further elucidate a more comprehensive understanding of this condition.

Hormonal influences have been suggested as a potential trigger for steatocystoma growth.^4,13 This condition is associated with dysfunction of the sebaceous glands, and, correspondingly, the incidence of disease is highest in pubertal patients, in whom androgen levels and sebum production are elevated.^4,13,14 Two cases of transgender men taking testosterone therapy presenting with steatocystomas provide additional clinical support for this association.¹⁵

Additionally, the use of immunomodulatory agents, such as ustekinumab (anti–interleukin 12/interleukin 23), has been shown to trigger SM. It is predicted that the reduced expression of certain interferons and interleukins may lead to downstream consequences in the keratin 17 pathway and lead to SM lesion formation in genetically susceptible individuals.¹⁶ Targeting these potential causes in the future may prove efficacious in the secondary prevention of familial SM manifestation or exacerbations.

Mutations in the KRT17 gene also have been implicated in pachyonychia congenita type 2 (PC-2).⁴ Marked by extensive systemic hyperkeratosis, PC-2 has been observed to coincide with SM in certain patients.^4,5 Interestingly, the location of the KRT17 mutations are identical in both PC-2 and SM.⁴ Although most individuals with hereditary SM do not exhibit the characteristic features of PC-2, mild nail and dental abnormalities have been observed in some SM cases.^4,10 This relationship suggests that SM may be a less severe variant of PC-2 or part of a complex polygenetic spectrum of disease.¹⁰ Further research is imperative to determine the exact nature and extent of the relationship between these conditions.

Clinical Manifestations

Steatocystomas are flesh-colored subcutaneous cysts that range in size from less than 3 mm to larger than 3 cm in diameter (Figure). They form within a single pilosebaceous unit and typically display firm attachment due to their origination in the dermis.^2,7,17 Steatocystomas generally contain lipid material, and less frequently, keratin and hair shafts, distinguishing them as the only “true” sebaceous cysts.¹⁸ Their color can range from flesh-toned to yellow, with reports of occasional dark-blue shades and calcifications.^19,20 Steatocystomas can persist indefinitely, and they usually are asymptomatic.

Diagnosis of steatocystoma is confirmed by biopsy.⁴ Steatocystomas are characterized by a dermal cyst lined by stratified squamous cell epithelium (eFigures 1 and 2).²¹ Classically they feature flattened sebaceous lobules, multinucleated giant cells, and abortive hair follicles. The lining of these cysts is marked by lymphocytic infiltrate and a dense, wrinkled, eosinophilic keratin cuticle that replaces the granular layer.²² The cyst maintains an epidermal connection through a follicular infundibulum characterized by clumps of keratinocytes, sebocytes, corneocytes, and/or hair follicles.⁷ Aspirated contents reveal crystalline structures and anucleate squamous cells upon microscopic analysis. That being said, variable histologic findings of steatocystomas have been described.²³

Steatocystoma simplex, as the name implies, classifies a single isolated steatocystoma. This subtype exhibits similar histopathologic and clinical features to the other subtypes of steatocystomas. Notably, SS is not associated with a genetic mutation and is not an inherited condition within families.⁵ Steatocystoma multiplex manifests with many steatocystomas, often distributed widely across the body.^3,4 The chest, axillae, and groin are the most common locations; however, these cysts can manifest on the face, back, abdomen, and extremities.^4,18-22 Rare occurrences of SM limited to the face, scalp, and distal extremities have been documented.^18,21,24,25 Due to the possibility of an autosomal-dominant inheritance, it is advisable to take a comprehensive family history in patients for whom SM is in the differential.¹⁷

Steatocystoma multiplex—especially familial variants—has been shown to develop in conjunction with other dermatologic conditions, including eruptive vellus hair (EVH) cysts, persistent infantile milia, and epidermoid/dermoid cysts.²⁶ While some investigators regard these as separate entities due to their varied genetic etiology, it has been suggested that these conditions may be related and that the diagnosis is determined by the location of cyst origin along the sebaceous ducts.^26,27 Other dermatologic conditions and lesions that frequently manifest comorbidly with SM include hidrocystomas, syringomas, pilonidal cysts, lichen planus, nodulocystic acne, trichotillomania, trichoblastomas, trichoepithelioma, HS, keratoacanthomas, acrokeratosis verruciformis of Hopf, and embryonal hair formation. Steatocystoma multiplex, manifesting comorbidly with dental and orofacial malformations (eg, partial noneruption of secondary teeth, natal and defective teeth, and bilateral preauricular sinuses) has been classified as SM natal teeth syndrome.⁶

Steatocystoma multiplex suppurativa is a rare and serious variant of SM characterized by inflammation, cyst rupture, sinus tract formation, and scarring.²⁴ Patients with SMS typically have multiple intact SM cysts, which can aid in differentiation from HS.^2,24 Steatocystoma multiplex suppurativa is associated with more complications than SS and SM, including cyst perforation, development of purulent and/or foul-smelling discharge, infection, scarring, pain, and overall discomfort.²

Given its rarity and the potential manifestations that overlap with other conditions, steatocystomas easily can be misdiagnosed. In some clinical instances, EVHs may share similar characteristics with SM; however, certain distinguishing features exist, including a central tuft of protruding hairs and different expressed contents, such as the vellus hair shafts, from the cyst’s lumen.²⁸ Furthermore, histologic examination of EVHs reveals epidermoid keratinization of the lining as well as a lack of sebaceous glands within the wall.^28,29 Other similar conditions include epidermoid cysts, pilar cysts, lipomas, epidermal inclusion cysts, dermoid cysts, sebaceous hyperplasia, folliculitis, xanthomas, neurofibromatosis, and syringomas.³⁰ Occasionally, SMS can be mistaken for HS or acne conglobata, and SM lesions with a facial distribution can mimic acne vulgaris.^1,31 These conditions should be excluded before a diagnosis of SS, SM, or SMS is made. 

Importantly, SM is visually indistinguishable from subcutaneous metastasis on physical examination, and there are reports of oncologic conditions (eg, pulmonary adenocarcinoma metastasized to the skin) being mistaken for SS or SM.³² Therefore, a thorough clinical examination, histopathologic analysis, and potential use of other imaging modalities such as ultrasonography (US) are needed to ensure an accurate diagnosis.

Ultrasonography has demonstrated utility in diagnosing steatocystomas.^33-35 Steatocystomas have incidentally been found on routine mammograms and can demonstrate well-defined circular nodules with radiolucent characteristics and a thin radiodense outline.^33,36 Homogeneous hypoechoic nodules within the dermis without posterior acoustic features generally are observed (eFigure 3).^33,37 In patients declining biopsy, US may be useful in further characterization of an unknown lesion. Color Doppler US can be used to distinguish SMS from HS. Specifically, SM typically exhibits an absence of Doppler signaling due to a lack of vascularity, providing a helpful diagnostic clue for the SMS variant.³³

Management and Treatment Options

There is no established standard treatment for steatocystomas; therefore, the approach to management is contingent on clinical presentation and patient preferences. Various medical, surgical, and laser management options are available, each with its own advantages and limitations. Treatment of SM is difficult due to the large number of lesions.³⁸ In many cases, continued observation is a viable treatment option, as most SS and SM lesions are asymptomatic; however, cosmetic concerns can be debilitating for patients with SM and may warrant intervention.³⁹ More extensive medical and surgical management often are necessary in SMS due to associated morbidity. Discussing options and goals as well as setting realistic expectations with the patient are essential in determining the optimal approach.

Medical Management—In medical literature, oral isotretinoin (13-cis-retinoic acid) has been the mainstay of therapy for steatocystoma, as its effect on the size and activity of sebaceous glands is hypothesized to decrease disease activity.^38,40 Interventional studies and case reports have exhibited varying degrees of effectiveness.^1,38-41 Some reports depict a reduction in the formation of new lesions and a decrease in the size of pre-existing lesions, some show mild delayed therapeutic efficacy, and others suggest exacerbation of the condition.^1,38-41 This outcome variability is attributed to isotretinoin’s preferential efficacy in treating inflammatory lesions.^40,42

Tetracycline derivatives and intralesional steroid injections also have been employed with some efficacy in patients with focal inflammatory SM and SMS.⁴³ There is limited evidence on the long-term outcomes of these interventions, and intralesional injections often are not recommended in conditions such as SM, in which there are many lesions present.

Surgical Management—Minimally invasive surgical procedures including drainage and resections have been used with varying efficacy in SS and SM. Typically, a 2- to 3-mm incision or sharp-tipped cautery is employed to puncture the cyst. Alternatively, radiofrequency probes with a 2.4-MHz frequency setting have been used to minimize incision size.⁴⁴ The contents then are expressed with manual pressure or forceps, and the cyst sac is extracted using forceps and/or a vein hook (eFigure 4).^44,45 The specific surgical techniques and their respective advantages and limitations are summarized in the eTable. Reported advantages and limitations of surgical techniques are derived from information provided by the authors of steatocystoma case reports, which are based on observations of a very limited sample size.

Laser Treatment—Various laser modalities have been used in the management of steatocystomas, including carbon dioxide lasers, erbium-doped yttrium aluminum garnet lasers, 1450-nm diode plus 1550-nm fractionated erbium-doped fiber lasers, and 1927-nm diode lasers.^54,55-57 These lasers are used to perforate the cyst before extirpation and have displayed advantages in minimizing scar length.⁵⁸ The super-pulse mode of carbon dioxide lasers demonstrates efficacy with minimal scarring and recurrence, and this mode is preferred to minimize thermal damage.^54,59 Furthermore, this modality can be especially useful in patients whose condition is refractory to other noninvasive options.⁵⁹ Similarly, the erbium-doped yttrium aluminum garnet laser was well tolerated with no complications noted.⁵⁵ The 1927-nm diode laser also displayed good outcomes as well as no recurrence.⁵⁷ With laser use, it is important to note that multiple treatments are needed to see optimal outcomes.⁵⁴ Moreover, laser settings must be carefully considered, especially in patients with Fitzpatrick skin type III or higher, and topical anti-inflammatory agents should be considered posttreatment to minimize complications.^54,59,60

Recommendations

For management of SS, we recommend conservative therapy of watchful observation, as scarring or postinflammatory pigment change may be brought on by medical or surgical therapy; however, if SS is cosmetically bothersome, laser or surgical excision can be done (eFigure 4).^4,43-53 It is important to counsel the patient on risks/benefits. For SM, watchful observation also is indicated; however, systemic therapies aimed at prevention may be the most efficacious by limiting disease progression, and oral tetracycline or isotretinoin may be tried.⁴ Tetracyclines have the risk for photosensitivity and are teratogenic, while isotretinoin is extremely teratogenic, requires laboratory monitoring and regular pregnancy tests in women, and often causes substantial mucosal dryness. If lesions are bothersome or refractory to these therapies, intralesional steroids or surgical/laser procedures can be tried throughout multiple visits.^43-53 For SMS, systemic therapies frequently are recommended. The risks of systemic tetracycline and isotretinoin therapies must be discussed. Patients with treatment-refractory SMS may require surgical excision or deroofing of sinus tracts.^43-53 This management is similar to that of HS and must be tailored to the patient.

Conclusion

Overall, steatocystomas are a relatively rare pathology, with a limited consensus on their etiology and management. This review summarizes the current knowledge on the condition to support clinicians in diagnosis and management, ranging from watchful waiting to surgical removal. By individualizing treatment plans, clinicians ultimately can optimize outcomes in patients with steatocystomas.

Steatocystomas are small sebum-filled cysts that typically manifest in the dermis and originate from sebaceous follicles. Although commonly asymptomatic, these lesions can manifest with pruritus or become infected, predisposing patients to further complications.¹ Steatocystomas can manifest as single (steatocystoma simplex [SS]) or numerous (steatocystoma multiplex [SM]) lesions; the lesions also can spontaneously rupture with characteristics that resemble hidradenitis suppurativa (HS)(steatocystoma multiplex suppurativa [SMS]).^1,2

Steatocystomas are relatively rare, and there is limited consensus in the published literature on the etiology and management of this condition. In this article, we present a comprehensive review of steatocystomas in the current literature. We highlight important features to consider when making the diagnosis and also offer recommendations for best-practice treatment.

Historical Background

Although not explicitly identified by name, the first documentation of steatocystomas is a case report published in 1873. In this account, the author described a patient who presented with approximately 250 flesh-colored dermal cysts across the body that varied in size.³ In 1899, the term steatocystoma multiple—derived from Greek roots meaning “fatty bag”—was first used.⁴

In 1982, almost a century later, Brownstein⁵ reported some of the earliest cases of SS. This solitary subtype is identical to SM on a microscopic level; however, unlike SM, this variant occurs as a single lesion that typically forms in adulthood and in the absence of family history. Other benign adnexal tumors (eg, pilomatricomas, pilar cysts, and sebaceous hyperplasias) also can manifest as either solitary or multiple lesions.

In 1976, McDonald and Reed⁶ reported the first known cases of patients with both SM and HS. At the time, the co-occurrence of these conditions was viewed as coincidental, but there were postulations of a shared inflammatory process and hereditary link⁶; it was not until 1982 that the term steatocystoma multiplex suppurativum was coined to describe this variant.⁷ Although rare, there have been multiple documented instances of SMS since. It has been suggested that the convergence of these conditions may indicate a shared follicular proliferation defect.⁸ Ongoing investigation is warranted to explain the underlying pathogenesis of this unique variant.

Epidemiology

The available epidemiologic data primarily relate to SM, the most common steatocystoma variant. Nevertheless, SM is a relatively rare condition, and the exact incidence and prevalence remain unknown.^8,9 Steatocystomas typically manifest in the first and second decades of life and have been observed in patients of both sexes, with studies demonstrating no notable sex bias.^4,9

Etiology and Pathophysiology

Steatocystomas can occur sporadically or may be inherited as an autosomal-dominant condition.⁴ Typically, SS tends to manifest as an isolated occurrence without any inherent genetic predisposition.⁵ Alternatively, SM may develop sporadically or be associated with a mutation in the keratin 17 gene (KRT17).⁴ Steatocystoma multiplex also has been associated with at least 4 different missense mutations, including N92H, R94H, and R94C, located on the long (q) arm of chromosome 17.^4,10-12

The keratin 17 gene is responsible for encoding the keratin 17 protein, a type I intermediate filament predominantly synthesized in the basal cells of epithelial tissue. This fibrous structural protein can regulate many processes, including inflammation and cell proliferation, and is found in regions such as the sebaceous glands, hair follicles, and eccrine sweat glands. Overexpression of KRT17 has been suggested in other cutaneous conditions, most notably psoriasis.¹² Despite KRT17’s many roles, it remains unclear why SM typically manifests with a myriad of sebum-containing cysts as the primary symptom.¹² Continued investigation into the genetic underpinnings of SM and the keratin 17 protein is necessary to further elucidate a more comprehensive understanding of this condition.

Hormonal influences have been suggested as a potential trigger for steatocystoma growth.^4,13 This condition is associated with dysfunction of the sebaceous glands, and, correspondingly, the incidence of disease is highest in pubertal patients, in whom androgen levels and sebum production are elevated.^4,13,14 Two cases of transgender men taking testosterone therapy presenting with steatocystomas provide additional clinical support for this association.¹⁵

Additionally, the use of immunomodulatory agents, such as ustekinumab (anti–interleukin 12/interleukin 23), has been shown to trigger SM. It is predicted that the reduced expression of certain interferons and interleukins may lead to downstream consequences in the keratin 17 pathway and lead to SM lesion formation in genetically susceptible individuals.¹⁶ Targeting these potential causes in the future may prove efficacious in the secondary prevention of familial SM manifestation or exacerbations.

Mutations in the KRT17 gene also have been implicated in pachyonychia congenita type 2 (PC-2).⁴ Marked by extensive systemic hyperkeratosis, PC-2 has been observed to coincide with SM in certain patients.^4,5 Interestingly, the location of the KRT17 mutations are identical in both PC-2 and SM.⁴ Although most individuals with hereditary SM do not exhibit the characteristic features of PC-2, mild nail and dental abnormalities have been observed in some SM cases.^4,10 This relationship suggests that SM may be a less severe variant of PC-2 or part of a complex polygenetic spectrum of disease.¹⁰ Further research is imperative to determine the exact nature and extent of the relationship between these conditions.

Clinical Manifestations

Steatocystomas are flesh-colored subcutaneous cysts that range in size from less than 3 mm to larger than 3 cm in diameter (Figure). They form within a single pilosebaceous unit and typically display firm attachment due to their origination in the dermis.^2,7,17 Steatocystomas generally contain lipid material, and less frequently, keratin and hair shafts, distinguishing them as the only “true” sebaceous cysts.¹⁸ Their color can range from flesh-toned to yellow, with reports of occasional dark-blue shades and calcifications.^19,20 Steatocystomas can persist indefinitely, and they usually are asymptomatic.

Diagnosis of steatocystoma is confirmed by biopsy.⁴ Steatocystomas are characterized by a dermal cyst lined by stratified squamous cell epithelium (eFigures 1 and 2).²¹ Classically they feature flattened sebaceous lobules, multinucleated giant cells, and abortive hair follicles. The lining of these cysts is marked by lymphocytic infiltrate and a dense, wrinkled, eosinophilic keratin cuticle that replaces the granular layer.²² The cyst maintains an epidermal connection through a follicular infundibulum characterized by clumps of keratinocytes, sebocytes, corneocytes, and/or hair follicles.⁷ Aspirated contents reveal crystalline structures and anucleate squamous cells upon microscopic analysis. That being said, variable histologic findings of steatocystomas have been described.²³

Steatocystoma simplex, as the name implies, classifies a single isolated steatocystoma. This subtype exhibits similar histopathologic and clinical features to the other subtypes of steatocystomas. Notably, SS is not associated with a genetic mutation and is not an inherited condition within families.⁵ Steatocystoma multiplex manifests with many steatocystomas, often distributed widely across the body.^3,4 The chest, axillae, and groin are the most common locations; however, these cysts can manifest on the face, back, abdomen, and extremities.^4,18-22 Rare occurrences of SM limited to the face, scalp, and distal extremities have been documented.^18,21,24,25 Due to the possibility of an autosomal-dominant inheritance, it is advisable to take a comprehensive family history in patients for whom SM is in the differential.¹⁷

Steatocystoma multiplex—especially familial variants—has been shown to develop in conjunction with other dermatologic conditions, including eruptive vellus hair (EVH) cysts, persistent infantile milia, and epidermoid/dermoid cysts.²⁶ While some investigators regard these as separate entities due to their varied genetic etiology, it has been suggested that these conditions may be related and that the diagnosis is determined by the location of cyst origin along the sebaceous ducts.^26,27 Other dermatologic conditions and lesions that frequently manifest comorbidly with SM include hidrocystomas, syringomas, pilonidal cysts, lichen planus, nodulocystic acne, trichotillomania, trichoblastomas, trichoepithelioma, HS, keratoacanthomas, acrokeratosis verruciformis of Hopf, and embryonal hair formation. Steatocystoma multiplex, manifesting comorbidly with dental and orofacial malformations (eg, partial noneruption of secondary teeth, natal and defective teeth, and bilateral preauricular sinuses) has been classified as SM natal teeth syndrome.⁶

Steatocystoma multiplex suppurativa is a rare and serious variant of SM characterized by inflammation, cyst rupture, sinus tract formation, and scarring.²⁴ Patients with SMS typically have multiple intact SM cysts, which can aid in differentiation from HS.^2,24 Steatocystoma multiplex suppurativa is associated with more complications than SS and SM, including cyst perforation, development of purulent and/or foul-smelling discharge, infection, scarring, pain, and overall discomfort.²

Given its rarity and the potential manifestations that overlap with other conditions, steatocystomas easily can be misdiagnosed. In some clinical instances, EVHs may share similar characteristics with SM; however, certain distinguishing features exist, including a central tuft of protruding hairs and different expressed contents, such as the vellus hair shafts, from the cyst’s lumen.²⁸ Furthermore, histologic examination of EVHs reveals epidermoid keratinization of the lining as well as a lack of sebaceous glands within the wall.^28,29 Other similar conditions include epidermoid cysts, pilar cysts, lipomas, epidermal inclusion cysts, dermoid cysts, sebaceous hyperplasia, folliculitis, xanthomas, neurofibromatosis, and syringomas.³⁰ Occasionally, SMS can be mistaken for HS or acne conglobata, and SM lesions with a facial distribution can mimic acne vulgaris.^1,31 These conditions should be excluded before a diagnosis of SS, SM, or SMS is made. 

Importantly, SM is visually indistinguishable from subcutaneous metastasis on physical examination, and there are reports of oncologic conditions (eg, pulmonary adenocarcinoma metastasized to the skin) being mistaken for SS or SM.³² Therefore, a thorough clinical examination, histopathologic analysis, and potential use of other imaging modalities such as ultrasonography (US) are needed to ensure an accurate diagnosis.

Ultrasonography has demonstrated utility in diagnosing steatocystomas.^33-35 Steatocystomas have incidentally been found on routine mammograms and can demonstrate well-defined circular nodules with radiolucent characteristics and a thin radiodense outline.^33,36 Homogeneous hypoechoic nodules within the dermis without posterior acoustic features generally are observed (eFigure 3).^33,37 In patients declining biopsy, US may be useful in further characterization of an unknown lesion. Color Doppler US can be used to distinguish SMS from HS. Specifically, SM typically exhibits an absence of Doppler signaling due to a lack of vascularity, providing a helpful diagnostic clue for the SMS variant.³³

Management and Treatment Options

There is no established standard treatment for steatocystomas; therefore, the approach to management is contingent on clinical presentation and patient preferences. Various medical, surgical, and laser management options are available, each with its own advantages and limitations. Treatment of SM is difficult due to the large number of lesions.³⁸ In many cases, continued observation is a viable treatment option, as most SS and SM lesions are asymptomatic; however, cosmetic concerns can be debilitating for patients with SM and may warrant intervention.³⁹ More extensive medical and surgical management often are necessary in SMS due to associated morbidity. Discussing options and goals as well as setting realistic expectations with the patient are essential in determining the optimal approach.

Medical Management—In medical literature, oral isotretinoin (13-cis-retinoic acid) has been the mainstay of therapy for steatocystoma, as its effect on the size and activity of sebaceous glands is hypothesized to decrease disease activity.^38,40 Interventional studies and case reports have exhibited varying degrees of effectiveness.^1,38-41 Some reports depict a reduction in the formation of new lesions and a decrease in the size of pre-existing lesions, some show mild delayed therapeutic efficacy, and others suggest exacerbation of the condition.^1,38-41 This outcome variability is attributed to isotretinoin’s preferential efficacy in treating inflammatory lesions.^40,42

Tetracycline derivatives and intralesional steroid injections also have been employed with some efficacy in patients with focal inflammatory SM and SMS.⁴³ There is limited evidence on the long-term outcomes of these interventions, and intralesional injections often are not recommended in conditions such as SM, in which there are many lesions present.

Surgical Management—Minimally invasive surgical procedures including drainage and resections have been used with varying efficacy in SS and SM. Typically, a 2- to 3-mm incision or sharp-tipped cautery is employed to puncture the cyst. Alternatively, radiofrequency probes with a 2.4-MHz frequency setting have been used to minimize incision size.⁴⁴ The contents then are expressed with manual pressure or forceps, and the cyst sac is extracted using forceps and/or a vein hook (eFigure 4).^44,45 The specific surgical techniques and their respective advantages and limitations are summarized in the eTable. Reported advantages and limitations of surgical techniques are derived from information provided by the authors of steatocystoma case reports, which are based on observations of a very limited sample size.

Laser Treatment—Various laser modalities have been used in the management of steatocystomas, including carbon dioxide lasers, erbium-doped yttrium aluminum garnet lasers, 1450-nm diode plus 1550-nm fractionated erbium-doped fiber lasers, and 1927-nm diode lasers.^54,55-57 These lasers are used to perforate the cyst before extirpation and have displayed advantages in minimizing scar length.⁵⁸ The super-pulse mode of carbon dioxide lasers demonstrates efficacy with minimal scarring and recurrence, and this mode is preferred to minimize thermal damage.^54,59 Furthermore, this modality can be especially useful in patients whose condition is refractory to other noninvasive options.⁵⁹ Similarly, the erbium-doped yttrium aluminum garnet laser was well tolerated with no complications noted.⁵⁵ The 1927-nm diode laser also displayed good outcomes as well as no recurrence.⁵⁷ With laser use, it is important to note that multiple treatments are needed to see optimal outcomes.⁵⁴ Moreover, laser settings must be carefully considered, especially in patients with Fitzpatrick skin type III or higher, and topical anti-inflammatory agents should be considered posttreatment to minimize complications.^54,59,60

Recommendations

For management of SS, we recommend conservative therapy of watchful observation, as scarring or postinflammatory pigment change may be brought on by medical or surgical therapy; however, if SS is cosmetically bothersome, laser or surgical excision can be done (eFigure 4).^4,43-53 It is important to counsel the patient on risks/benefits. For SM, watchful observation also is indicated; however, systemic therapies aimed at prevention may be the most efficacious by limiting disease progression, and oral tetracycline or isotretinoin may be tried.⁴ Tetracyclines have the risk for photosensitivity and are teratogenic, while isotretinoin is extremely teratogenic, requires laboratory monitoring and regular pregnancy tests in women, and often causes substantial mucosal dryness. If lesions are bothersome or refractory to these therapies, intralesional steroids or surgical/laser procedures can be tried throughout multiple visits.^43-53 For SMS, systemic therapies frequently are recommended. The risks of systemic tetracycline and isotretinoin therapies must be discussed. Patients with treatment-refractory SMS may require surgical excision or deroofing of sinus tracts.^43-53 This management is similar to that of HS and must be tailored to the patient.

Conclusion

Overall, steatocystomas are a relatively rare pathology, with a limited consensus on their etiology and management. This review summarizes the current knowledge on the condition to support clinicians in diagnosis and management, ranging from watchful waiting to surgical removal. By individualizing treatment plans, clinicians ultimately can optimize outcomes in patients with steatocystomas.

Steatocystomas are small sebum-filled cysts that typically manifest in the dermis and originate from sebaceous follicles. Although commonly asymptomatic, these lesions can manifest with pruritus or become infected, predisposing patients to further complications.¹ Steatocystomas can manifest as single (steatocystoma simplex [SS]) or numerous (steatocystoma multiplex [SM]) lesions; the lesions also can spontaneously rupture with characteristics that resemble hidradenitis suppurativa (HS)(steatocystoma multiplex suppurativa [SMS]).^1,2

Steatocystomas are relatively rare, and there is limited consensus in the published literature on the etiology and management of this condition. In this article, we present a comprehensive review of steatocystomas in the current literature. We highlight important features to consider when making the diagnosis and also offer recommendations for best-practice treatment.

Historical Background

Although not explicitly identified by name, the first documentation of steatocystomas is a case report published in 1873. In this account, the author described a patient who presented with approximately 250 flesh-colored dermal cysts across the body that varied in size.³ In 1899, the term steatocystoma multiple—derived from Greek roots meaning “fatty bag”—was first used.⁴

In 1982, almost a century later, Brownstein⁵ reported some of the earliest cases of SS. This solitary subtype is identical to SM on a microscopic level; however, unlike SM, this variant occurs as a single lesion that typically forms in adulthood and in the absence of family history. Other benign adnexal tumors (eg, pilomatricomas, pilar cysts, and sebaceous hyperplasias) also can manifest as either solitary or multiple lesions.

In 1976, McDonald and Reed⁶ reported the first known cases of patients with both SM and HS. At the time, the co-occurrence of these conditions was viewed as coincidental, but there were postulations of a shared inflammatory process and hereditary link⁶; it was not until 1982 that the term steatocystoma multiplex suppurativum was coined to describe this variant.⁷ Although rare, there have been multiple documented instances of SMS since. It has been suggested that the convergence of these conditions may indicate a shared follicular proliferation defect.⁸ Ongoing investigation is warranted to explain the underlying pathogenesis of this unique variant.

Epidemiology

The available epidemiologic data primarily relate to SM, the most common steatocystoma variant. Nevertheless, SM is a relatively rare condition, and the exact incidence and prevalence remain unknown.^8,9 Steatocystomas typically manifest in the first and second decades of life and have been observed in patients of both sexes, with studies demonstrating no notable sex bias.^4,9

Etiology and Pathophysiology

Steatocystomas can occur sporadically or may be inherited as an autosomal-dominant condition.⁴ Typically, SS tends to manifest as an isolated occurrence without any inherent genetic predisposition.⁵ Alternatively, SM may develop sporadically or be associated with a mutation in the keratin 17 gene (KRT17).⁴ Steatocystoma multiplex also has been associated with at least 4 different missense mutations, including N92H, R94H, and R94C, located on the long (q) arm of chromosome 17.^4,10-12

The keratin 17 gene is responsible for encoding the keratin 17 protein, a type I intermediate filament predominantly synthesized in the basal cells of epithelial tissue. This fibrous structural protein can regulate many processes, including inflammation and cell proliferation, and is found in regions such as the sebaceous glands, hair follicles, and eccrine sweat glands. Overexpression of KRT17 has been suggested in other cutaneous conditions, most notably psoriasis.¹² Despite KRT17’s many roles, it remains unclear why SM typically manifests with a myriad of sebum-containing cysts as the primary symptom.¹² Continued investigation into the genetic underpinnings of SM and the keratin 17 protein is necessary to further elucidate a more comprehensive understanding of this condition.

Hormonal influences have been suggested as a potential trigger for steatocystoma growth.^4,13 This condition is associated with dysfunction of the sebaceous glands, and, correspondingly, the incidence of disease is highest in pubertal patients, in whom androgen levels and sebum production are elevated.^4,13,14 Two cases of transgender men taking testosterone therapy presenting with steatocystomas provide additional clinical support for this association.¹⁵

Additionally, the use of immunomodulatory agents, such as ustekinumab (anti–interleukin 12/interleukin 23), has been shown to trigger SM. It is predicted that the reduced expression of certain interferons and interleukins may lead to downstream consequences in the keratin 17 pathway and lead to SM lesion formation in genetically susceptible individuals.¹⁶ Targeting these potential causes in the future may prove efficacious in the secondary prevention of familial SM manifestation or exacerbations.

Mutations in the KRT17 gene also have been implicated in pachyonychia congenita type 2 (PC-2).⁴ Marked by extensive systemic hyperkeratosis, PC-2 has been observed to coincide with SM in certain patients.^4,5 Interestingly, the location of the KRT17 mutations are identical in both PC-2 and SM.⁴ Although most individuals with hereditary SM do not exhibit the characteristic features of PC-2, mild nail and dental abnormalities have been observed in some SM cases.^4,10 This relationship suggests that SM may be a less severe variant of PC-2 or part of a complex polygenetic spectrum of disease.¹⁰ Further research is imperative to determine the exact nature and extent of the relationship between these conditions.

Clinical Manifestations

Steatocystomas are flesh-colored subcutaneous cysts that range in size from less than 3 mm to larger than 3 cm in diameter (Figure). They form within a single pilosebaceous unit and typically display firm attachment due to their origination in the dermis.^2,7,17 Steatocystomas generally contain lipid material, and less frequently, keratin and hair shafts, distinguishing them as the only “true” sebaceous cysts.¹⁸ Their color can range from flesh-toned to yellow, with reports of occasional dark-blue shades and calcifications.^19,20 Steatocystomas can persist indefinitely, and they usually are asymptomatic.

Diagnosis of steatocystoma is confirmed by biopsy.⁴ Steatocystomas are characterized by a dermal cyst lined by stratified squamous cell epithelium (eFigures 1 and 2).²¹ Classically they feature flattened sebaceous lobules, multinucleated giant cells, and abortive hair follicles. The lining of these cysts is marked by lymphocytic infiltrate and a dense, wrinkled, eosinophilic keratin cuticle that replaces the granular layer.²² The cyst maintains an epidermal connection through a follicular infundibulum characterized by clumps of keratinocytes, sebocytes, corneocytes, and/or hair follicles.⁷ Aspirated contents reveal crystalline structures and anucleate squamous cells upon microscopic analysis. That being said, variable histologic findings of steatocystomas have been described.²³

Steatocystoma simplex, as the name implies, classifies a single isolated steatocystoma. This subtype exhibits similar histopathologic and clinical features to the other subtypes of steatocystomas. Notably, SS is not associated with a genetic mutation and is not an inherited condition within families.⁵ Steatocystoma multiplex manifests with many steatocystomas, often distributed widely across the body.^3,4 The chest, axillae, and groin are the most common locations; however, these cysts can manifest on the face, back, abdomen, and extremities.^4,18-22 Rare occurrences of SM limited to the face, scalp, and distal extremities have been documented.^18,21,24,25 Due to the possibility of an autosomal-dominant inheritance, it is advisable to take a comprehensive family history in patients for whom SM is in the differential.¹⁷

Steatocystoma multiplex—especially familial variants—has been shown to develop in conjunction with other dermatologic conditions, including eruptive vellus hair (EVH) cysts, persistent infantile milia, and epidermoid/dermoid cysts.²⁶ While some investigators regard these as separate entities due to their varied genetic etiology, it has been suggested that these conditions may be related and that the diagnosis is determined by the location of cyst origin along the sebaceous ducts.^26,27 Other dermatologic conditions and lesions that frequently manifest comorbidly with SM include hidrocystomas, syringomas, pilonidal cysts, lichen planus, nodulocystic acne, trichotillomania, trichoblastomas, trichoepithelioma, HS, keratoacanthomas, acrokeratosis verruciformis of Hopf, and embryonal hair formation. Steatocystoma multiplex, manifesting comorbidly with dental and orofacial malformations (eg, partial noneruption of secondary teeth, natal and defective teeth, and bilateral preauricular sinuses) has been classified as SM natal teeth syndrome.⁶

Steatocystoma multiplex suppurativa is a rare and serious variant of SM characterized by inflammation, cyst rupture, sinus tract formation, and scarring.²⁴ Patients with SMS typically have multiple intact SM cysts, which can aid in differentiation from HS.^2,24 Steatocystoma multiplex suppurativa is associated with more complications than SS and SM, including cyst perforation, development of purulent and/or foul-smelling discharge, infection, scarring, pain, and overall discomfort.²

Given its rarity and the potential manifestations that overlap with other conditions, steatocystomas easily can be misdiagnosed. In some clinical instances, EVHs may share similar characteristics with SM; however, certain distinguishing features exist, including a central tuft of protruding hairs and different expressed contents, such as the vellus hair shafts, from the cyst’s lumen.²⁸ Furthermore, histologic examination of EVHs reveals epidermoid keratinization of the lining as well as a lack of sebaceous glands within the wall.^28,29 Other similar conditions include epidermoid cysts, pilar cysts, lipomas, epidermal inclusion cysts, dermoid cysts, sebaceous hyperplasia, folliculitis, xanthomas, neurofibromatosis, and syringomas.³⁰ Occasionally, SMS can be mistaken for HS or acne conglobata, and SM lesions with a facial distribution can mimic acne vulgaris.^1,31 These conditions should be excluded before a diagnosis of SS, SM, or SMS is made. 

Importantly, SM is visually indistinguishable from subcutaneous metastasis on physical examination, and there are reports of oncologic conditions (eg, pulmonary adenocarcinoma metastasized to the skin) being mistaken for SS or SM.³² Therefore, a thorough clinical examination, histopathologic analysis, and potential use of other imaging modalities such as ultrasonography (US) are needed to ensure an accurate diagnosis.

Ultrasonography has demonstrated utility in diagnosing steatocystomas.^33-35 Steatocystomas have incidentally been found on routine mammograms and can demonstrate well-defined circular nodules with radiolucent characteristics and a thin radiodense outline.^33,36 Homogeneous hypoechoic nodules within the dermis without posterior acoustic features generally are observed (eFigure 3).^33,37 In patients declining biopsy, US may be useful in further characterization of an unknown lesion. Color Doppler US can be used to distinguish SMS from HS. Specifically, SM typically exhibits an absence of Doppler signaling due to a lack of vascularity, providing a helpful diagnostic clue for the SMS variant.³³

Management and Treatment Options

There is no established standard treatment for steatocystomas; therefore, the approach to management is contingent on clinical presentation and patient preferences. Various medical, surgical, and laser management options are available, each with its own advantages and limitations. Treatment of SM is difficult due to the large number of lesions.³⁸ In many cases, continued observation is a viable treatment option, as most SS and SM lesions are asymptomatic; however, cosmetic concerns can be debilitating for patients with SM and may warrant intervention.³⁹ More extensive medical and surgical management often are necessary in SMS due to associated morbidity. Discussing options and goals as well as setting realistic expectations with the patient are essential in determining the optimal approach.

Medical Management—In medical literature, oral isotretinoin (13-cis-retinoic acid) has been the mainstay of therapy for steatocystoma, as its effect on the size and activity of sebaceous glands is hypothesized to decrease disease activity.^38,40 Interventional studies and case reports have exhibited varying degrees of effectiveness.^1,38-41 Some reports depict a reduction in the formation of new lesions and a decrease in the size of pre-existing lesions, some show mild delayed therapeutic efficacy, and others suggest exacerbation of the condition.^1,38-41 This outcome variability is attributed to isotretinoin’s preferential efficacy in treating inflammatory lesions.^40,42

Tetracycline derivatives and intralesional steroid injections also have been employed with some efficacy in patients with focal inflammatory SM and SMS.⁴³ There is limited evidence on the long-term outcomes of these interventions, and intralesional injections often are not recommended in conditions such as SM, in which there are many lesions present.

Surgical Management—Minimally invasive surgical procedures including drainage and resections have been used with varying efficacy in SS and SM. Typically, a 2- to 3-mm incision or sharp-tipped cautery is employed to puncture the cyst. Alternatively, radiofrequency probes with a 2.4-MHz frequency setting have been used to minimize incision size.⁴⁴ The contents then are expressed with manual pressure or forceps, and the cyst sac is extracted using forceps and/or a vein hook (eFigure 4).^44,45 The specific surgical techniques and their respective advantages and limitations are summarized in the eTable. Reported advantages and limitations of surgical techniques are derived from information provided by the authors of steatocystoma case reports, which are based on observations of a very limited sample size.

Laser Treatment—Various laser modalities have been used in the management of steatocystomas, including carbon dioxide lasers, erbium-doped yttrium aluminum garnet lasers, 1450-nm diode plus 1550-nm fractionated erbium-doped fiber lasers, and 1927-nm diode lasers.^54,55-57 These lasers are used to perforate the cyst before extirpation and have displayed advantages in minimizing scar length.⁵⁸ The super-pulse mode of carbon dioxide lasers demonstrates efficacy with minimal scarring and recurrence, and this mode is preferred to minimize thermal damage.^54,59 Furthermore, this modality can be especially useful in patients whose condition is refractory to other noninvasive options.⁵⁹ Similarly, the erbium-doped yttrium aluminum garnet laser was well tolerated with no complications noted.⁵⁵ The 1927-nm diode laser also displayed good outcomes as well as no recurrence.⁵⁷ With laser use, it is important to note that multiple treatments are needed to see optimal outcomes.⁵⁴ Moreover, laser settings must be carefully considered, especially in patients with Fitzpatrick skin type III or higher, and topical anti-inflammatory agents should be considered posttreatment to minimize complications.^54,59,60

Recommendations

For management of SS, we recommend conservative therapy of watchful observation, as scarring or postinflammatory pigment change may be brought on by medical or surgical therapy; however, if SS is cosmetically bothersome, laser or surgical excision can be done (eFigure 4).^4,43-53 It is important to counsel the patient on risks/benefits. For SM, watchful observation also is indicated; however, systemic therapies aimed at prevention may be the most efficacious by limiting disease progression, and oral tetracycline or isotretinoin may be tried.⁴ Tetracyclines have the risk for photosensitivity and are teratogenic, while isotretinoin is extremely teratogenic, requires laboratory monitoring and regular pregnancy tests in women, and often causes substantial mucosal dryness. If lesions are bothersome or refractory to these therapies, intralesional steroids or surgical/laser procedures can be tried throughout multiple visits.^43-53 For SMS, systemic therapies frequently are recommended. The risks of systemic tetracycline and isotretinoin therapies must be discussed. Patients with treatment-refractory SMS may require surgical excision or deroofing of sinus tracts.^43-53 This management is similar to that of HS and must be tailored to the patient.

Conclusion

Overall, steatocystomas are a relatively rare pathology, with a limited consensus on their etiology and management. This review summarizes the current knowledge on the condition to support clinicians in diagnosis and management, ranging from watchful waiting to surgical removal. By individualizing treatment plans, clinicians ultimately can optimize outcomes in patients with steatocystomas.