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The Diagnosis: Juvenile Xanthogranuloma

Juvenile xanthogranuloma (JXG) was first described in 1905 by Adamson1 as solitary or multiple plaquiform or nodular lesions that are yellow to yellowish brown. In 1954, Helwig and Hackney² coined the term juvenile xanthogranuloma to define this histiocytic cutaneous granulomatous tumor.

Juvenile xanthogranuloma is a rare dermatologic disorder that may be present at birth and primarily affects infants and young children. The benign lesions generally occur in the first 4 years of life, with a median age of onset of 2 years.³ Lesions range in size from millimeters to several centimeters in diameter.⁴ The skin of the head and neck is the most commonly involved site in JXG. The most frequent noncutaneous site of JXG involvement is the eye, particularly the iris, accounting for 0.4% of cases.^5,6 Extracutaneous sites such as the heart, liver, lungs, spleen, oral cavity, and brain also may be involved.⁴

Most children with JXG are asymptomatic. Skin lesions present as well-demarcated, rubbery, tan-orange papules or nodules. They usually are solitary, and multiple nodules can increase the risk for extracutaneous involvement.⁴ A case series of patients with neurofibromatosis type 1 showed 14 of 77 (18%) patients examined in the first year of life presented with JXG or other non–Langerhans cell histiocytosis.⁷ The adult form of cutaneous xanthogranuloma often presents with severe bronchial asthma.⁸

Histopathologic examination of a biopsy of the lesion typically demonstrates well-circumscribed nodules with dense infiltrates of polyhedral histiocytes with vaculoles.^3-7 In 85% of cases, Touton giant cells are present.^4,9 A prominent vascular network often is present, which was observed in our patient’s biopsy (Figure 1). Immunohistochemistry typically is positive for CD14, CD68, CD163, fascin, and factor XIIIa.^4,10 Classically, the cells are negative for S-100 and CD1a, which differentiates these lesions from Langerhans cell histiocytosis.^4-7,10 Our patient demonstrated scattered S-100–positive cells representing background dendritic cells and macrophages (Figure 2). The remainder of the clinical, morphologic, and immunophenotypic findings were consistent with non–Langerhans cell histiocytosis, specifically JXG.

Biopsy should be performed in all cases, and basic laboratory test results such as a complete blood cell count and basic metabolic panel also are appropriate. Routine referral of all patients with cutaneous JXG for ophthalmologic evaluation is not recommended.¹¹ Most patients with ocular involvement present with acute ocular concerns; asymptomatic eye involvement is rare. It is reasonable to consider referral to ophthalmology for patients younger than 2 years who present with multiple lesions, as they may have a higher risk for ocular involvement.¹¹

Juvenile xanthogranuloma usually is a benign disorder with management involving observation, as the lesions typically involute spontaneously.^3-7,9,10,12 Systemic or intralesional corticosteroids may be used for treatment in lesions that do not resolve. Ocular JXG refractory to steroid treatment has been managed in several cases with intravitreal bevacizumab.¹³ Additionally, surgical excision can be considered if malignancy is suspected, the lesion does not resolve with observation or steroid treatment, or the lesion is located near vital structures.^4-7,9-13

Spitz nevus presents as a single dome-shaped papule, but histology shows a symmetrical proliferation of spindle and epithelioid cells. Trachoma can present in and around the eye as a follicular hypertrophy but most commonly is seen in the conjunctiva. Dermoid cysts present as solitary subcutaneous cystic lesions; histology demonstrates a lining of keratinizing squamous epithelium with the presence of pilosebaceous structures. Dermatofibroma appears as a tan to reddish-brown papule in an area of prior minor trauma; pathology demonstrates an acanthotic epidermis with an underlying zone of normal papillary dermis and unencapsulated lesions with spindle cells overlapping in fascicles and whorls at the periphery.

The Diagnosis: Juvenile Xanthogranuloma

Juvenile xanthogranuloma (JXG) was first described in 1905 by Adamson1 as solitary or multiple plaquiform or nodular lesions that are yellow to yellowish brown. In 1954, Helwig and Hackney² coined the term juvenile xanthogranuloma to define this histiocytic cutaneous granulomatous tumor.

Juvenile xanthogranuloma is a rare dermatologic disorder that may be present at birth and primarily affects infants and young children. The benign lesions generally occur in the first 4 years of life, with a median age of onset of 2 years.³ Lesions range in size from millimeters to several centimeters in diameter.⁴ The skin of the head and neck is the most commonly involved site in JXG. The most frequent noncutaneous site of JXG involvement is the eye, particularly the iris, accounting for 0.4% of cases.^5,6 Extracutaneous sites such as the heart, liver, lungs, spleen, oral cavity, and brain also may be involved.⁴

Most children with JXG are asymptomatic. Skin lesions present as well-demarcated, rubbery, tan-orange papules or nodules. They usually are solitary, and multiple nodules can increase the risk for extracutaneous involvement.⁴ A case series of patients with neurofibromatosis type 1 showed 14 of 77 (18%) patients examined in the first year of life presented with JXG or other non–Langerhans cell histiocytosis.⁷ The adult form of cutaneous xanthogranuloma often presents with severe bronchial asthma.⁸

Histopathologic examination of a biopsy of the lesion typically demonstrates well-circumscribed nodules with dense infiltrates of polyhedral histiocytes with vaculoles.^3-7 In 85% of cases, Touton giant cells are present.^4,9 A prominent vascular network often is present, which was observed in our patient’s biopsy (Figure 1). Immunohistochemistry typically is positive for CD14, CD68, CD163, fascin, and factor XIIIa.^4,10 Classically, the cells are negative for S-100 and CD1a, which differentiates these lesions from Langerhans cell histiocytosis.^4-7,10 Our patient demonstrated scattered S-100–positive cells representing background dendritic cells and macrophages (Figure 2). The remainder of the clinical, morphologic, and immunophenotypic findings were consistent with non–Langerhans cell histiocytosis, specifically JXG.

Biopsy should be performed in all cases, and basic laboratory test results such as a complete blood cell count and basic metabolic panel also are appropriate. Routine referral of all patients with cutaneous JXG for ophthalmologic evaluation is not recommended.¹¹ Most patients with ocular involvement present with acute ocular concerns; asymptomatic eye involvement is rare. It is reasonable to consider referral to ophthalmology for patients younger than 2 years who present with multiple lesions, as they may have a higher risk for ocular involvement.¹¹

Juvenile xanthogranuloma usually is a benign disorder with management involving observation, as the lesions typically involute spontaneously.^3-7,9,10,12 Systemic or intralesional corticosteroids may be used for treatment in lesions that do not resolve. Ocular JXG refractory to steroid treatment has been managed in several cases with intravitreal bevacizumab.¹³ Additionally, surgical excision can be considered if malignancy is suspected, the lesion does not resolve with observation or steroid treatment, or the lesion is located near vital structures.^4-7,9-13

Spitz nevus presents as a single dome-shaped papule, but histology shows a symmetrical proliferation of spindle and epithelioid cells. Trachoma can present in and around the eye as a follicular hypertrophy but most commonly is seen in the conjunctiva. Dermoid cysts present as solitary subcutaneous cystic lesions; histology demonstrates a lining of keratinizing squamous epithelium with the presence of pilosebaceous structures. Dermatofibroma appears as a tan to reddish-brown papule in an area of prior minor trauma; pathology demonstrates an acanthotic epidermis with an underlying zone of normal papillary dermis and unencapsulated lesions with spindle cells overlapping in fascicles and whorls at the periphery.

The Diagnosis: Juvenile Xanthogranuloma

Juvenile xanthogranuloma (JXG) was first described in 1905 by Adamson1 as solitary or multiple plaquiform or nodular lesions that are yellow to yellowish brown. In 1954, Helwig and Hackney² coined the term juvenile xanthogranuloma to define this histiocytic cutaneous granulomatous tumor.

Juvenile xanthogranuloma is a rare dermatologic disorder that may be present at birth and primarily affects infants and young children. The benign lesions generally occur in the first 4 years of life, with a median age of onset of 2 years.³ Lesions range in size from millimeters to several centimeters in diameter.⁴ The skin of the head and neck is the most commonly involved site in JXG. The most frequent noncutaneous site of JXG involvement is the eye, particularly the iris, accounting for 0.4% of cases.^5,6 Extracutaneous sites such as the heart, liver, lungs, spleen, oral cavity, and brain also may be involved.⁴

Most children with JXG are asymptomatic. Skin lesions present as well-demarcated, rubbery, tan-orange papules or nodules. They usually are solitary, and multiple nodules can increase the risk for extracutaneous involvement.⁴ A case series of patients with neurofibromatosis type 1 showed 14 of 77 (18%) patients examined in the first year of life presented with JXG or other non–Langerhans cell histiocytosis.⁷ The adult form of cutaneous xanthogranuloma often presents with severe bronchial asthma.⁸

Histopathologic examination of a biopsy of the lesion typically demonstrates well-circumscribed nodules with dense infiltrates of polyhedral histiocytes with vaculoles.^3-7 In 85% of cases, Touton giant cells are present.^4,9 A prominent vascular network often is present, which was observed in our patient’s biopsy (Figure 1). Immunohistochemistry typically is positive for CD14, CD68, CD163, fascin, and factor XIIIa.^4,10 Classically, the cells are negative for S-100 and CD1a, which differentiates these lesions from Langerhans cell histiocytosis.^4-7,10 Our patient demonstrated scattered S-100–positive cells representing background dendritic cells and macrophages (Figure 2). The remainder of the clinical, morphologic, and immunophenotypic findings were consistent with non–Langerhans cell histiocytosis, specifically JXG.

Biopsy should be performed in all cases, and basic laboratory test results such as a complete blood cell count and basic metabolic panel also are appropriate. Routine referral of all patients with cutaneous JXG for ophthalmologic evaluation is not recommended.¹¹ Most patients with ocular involvement present with acute ocular concerns; asymptomatic eye involvement is rare. It is reasonable to consider referral to ophthalmology for patients younger than 2 years who present with multiple lesions, as they may have a higher risk for ocular involvement.¹¹

Juvenile xanthogranuloma usually is a benign disorder with management involving observation, as the lesions typically involute spontaneously.^3-7,9,10,12 Systemic or intralesional corticosteroids may be used for treatment in lesions that do not resolve. Ocular JXG refractory to steroid treatment has been managed in several cases with intravitreal bevacizumab.¹³ Additionally, surgical excision can be considered if malignancy is suspected, the lesion does not resolve with observation or steroid treatment, or the lesion is located near vital structures.^4-7,9-13

Spitz nevus presents as a single dome-shaped papule, but histology shows a symmetrical proliferation of spindle and epithelioid cells. Trachoma can present in and around the eye as a follicular hypertrophy but most commonly is seen in the conjunctiva. Dermoid cysts present as solitary subcutaneous cystic lesions; histology demonstrates a lining of keratinizing squamous epithelium with the presence of pilosebaceous structures. Dermatofibroma appears as a tan to reddish-brown papule in an area of prior minor trauma; pathology demonstrates an acanthotic epidermis with an underlying zone of normal papillary dermis and unencapsulated lesions with spindle cells overlapping in fascicles and whorls at the periphery.

The Diagnosis: Milia En Plaque 

Biopsy results revealed a normal epidermis; the dermis showed multiple small cystic structures lined by a stratified squamous epithelium containing eosinophilic keratin surrounded by a mononuclear cell infiltrate and some melanophages (Figure).  

Milia en plaque was first described in 1903 by Balzer and Fouquet.¹ In 1978, Hubler et al² presented 2 cases with an asymptomatic, erythematous, and edematous plaque and white milialike lesions. On histopathology, they showed multiple cystic structures characterized by central laminated keratin and an intense polymorphic inflammatory reaction surrounding the cyst and epidermal appendages. Both patients were treated with topical tretinoin with complete response at 3 months. The authors suggested the term milia en plaque to describe this clinical entity.² 

Milia en plaque is described as an infrequent condition that more often presents on the head, neck, and trunk, as well as the periocular, periauricular, and perinasal areas. It has been reported to occur at any age³ but appears more frequently in middle-aged adults and females. A congenital case also has been reported.⁴ It has been associated with pseudoxanthoma elasticum, lichen planus, trauma, kidney transplant, and cyclosporine use, but it also can present in healthy individuals,³ as in our patient. No clear cause has been identified. 

Pathology is characteristic, with multiple cysts filled with keratin and surrounded by 2 or 3 layers of epithelial cells, associated with a mononuclear, nonlichenoid, mononuclear infiltrate.⁵ Structures similar to follicular infundibular tumors have been described, suggesting a common origin of follicular lesions as milia en plaque.⁶  

Treatment includes surgical excision, cryosurgery, dermabrasion, electrodesiccation, trichloroacetic acid, photodynamic therapy, CO₂ and erbium lasers, topical retinoids, minocycline, and etretinate.⁷ We performed a complete surgical excision in our patient.  

In acneform reactions, erythematous papules and pustules can be found on the cheeks and forehead. Nevus comedonicus appears during childhood and presents with multiple open comedones. Postinflammatory milia is present in chronic inflammatory pathologies such as porphyria cutanea tarda. Histopathologic findings in adnexal tumors show a benign proliferation of any cellular type of a cutaneous annex. 

Milia en plaque is an unusual but benign condition that is distinguished clinically by its characteristic presentation. 

The Diagnosis: Milia En Plaque 

Biopsy results revealed a normal epidermis; the dermis showed multiple small cystic structures lined by a stratified squamous epithelium containing eosinophilic keratin surrounded by a mononuclear cell infiltrate and some melanophages (Figure).  

Milia en plaque was first described in 1903 by Balzer and Fouquet.¹ In 1978, Hubler et al² presented 2 cases with an asymptomatic, erythematous, and edematous plaque and white milialike lesions. On histopathology, they showed multiple cystic structures characterized by central laminated keratin and an intense polymorphic inflammatory reaction surrounding the cyst and epidermal appendages. Both patients were treated with topical tretinoin with complete response at 3 months. The authors suggested the term milia en plaque to describe this clinical entity.² 

Milia en plaque is described as an infrequent condition that more often presents on the head, neck, and trunk, as well as the periocular, periauricular, and perinasal areas. It has been reported to occur at any age³ but appears more frequently in middle-aged adults and females. A congenital case also has been reported.⁴ It has been associated with pseudoxanthoma elasticum, lichen planus, trauma, kidney transplant, and cyclosporine use, but it also can present in healthy individuals,³ as in our patient. No clear cause has been identified. 

Pathology is characteristic, with multiple cysts filled with keratin and surrounded by 2 or 3 layers of epithelial cells, associated with a mononuclear, nonlichenoid, mononuclear infiltrate.⁵ Structures similar to follicular infundibular tumors have been described, suggesting a common origin of follicular lesions as milia en plaque.⁶  

Treatment includes surgical excision, cryosurgery, dermabrasion, electrodesiccation, trichloroacetic acid, photodynamic therapy, CO₂ and erbium lasers, topical retinoids, minocycline, and etretinate.⁷ We performed a complete surgical excision in our patient.  

In acneform reactions, erythematous papules and pustules can be found on the cheeks and forehead. Nevus comedonicus appears during childhood and presents with multiple open comedones. Postinflammatory milia is present in chronic inflammatory pathologies such as porphyria cutanea tarda. Histopathologic findings in adnexal tumors show a benign proliferation of any cellular type of a cutaneous annex. 

Milia en plaque is an unusual but benign condition that is distinguished clinically by its characteristic presentation. 

The Diagnosis: Milia En Plaque 

Biopsy results revealed a normal epidermis; the dermis showed multiple small cystic structures lined by a stratified squamous epithelium containing eosinophilic keratin surrounded by a mononuclear cell infiltrate and some melanophages (Figure).  

Milia en plaque was first described in 1903 by Balzer and Fouquet.¹ In 1978, Hubler et al² presented 2 cases with an asymptomatic, erythematous, and edematous plaque and white milialike lesions. On histopathology, they showed multiple cystic structures characterized by central laminated keratin and an intense polymorphic inflammatory reaction surrounding the cyst and epidermal appendages. Both patients were treated with topical tretinoin with complete response at 3 months. The authors suggested the term milia en plaque to describe this clinical entity.² 

Milia en plaque is described as an infrequent condition that more often presents on the head, neck, and trunk, as well as the periocular, periauricular, and perinasal areas. It has been reported to occur at any age³ but appears more frequently in middle-aged adults and females. A congenital case also has been reported.⁴ It has been associated with pseudoxanthoma elasticum, lichen planus, trauma, kidney transplant, and cyclosporine use, but it also can present in healthy individuals,³ as in our patient. No clear cause has been identified. 

Pathology is characteristic, with multiple cysts filled with keratin and surrounded by 2 or 3 layers of epithelial cells, associated with a mononuclear, nonlichenoid, mononuclear infiltrate.⁵ Structures similar to follicular infundibular tumors have been described, suggesting a common origin of follicular lesions as milia en plaque.⁶  

Treatment includes surgical excision, cryosurgery, dermabrasion, electrodesiccation, trichloroacetic acid, photodynamic therapy, CO₂ and erbium lasers, topical retinoids, minocycline, and etretinate.⁷ We performed a complete surgical excision in our patient.  

In acneform reactions, erythematous papules and pustules can be found on the cheeks and forehead. Nevus comedonicus appears during childhood and presents with multiple open comedones. Postinflammatory milia is present in chronic inflammatory pathologies such as porphyria cutanea tarda. Histopathologic findings in adnexal tumors show a benign proliferation of any cellular type of a cutaneous annex. 

Milia en plaque is an unusual but benign condition that is distinguished clinically by its characteristic presentation. 

The Diagnosis: Factitial Purpura 

Factitial dermatologic disorders are characterized by skin findings triggered by deliberate manipulation of the skin with objects to create lesions and feign signs of a dermatologic condition to seek emotional and psychological benefit.¹ The etiology of the lesions is unclear, and the patient's history of the injury is hollow.² Most often, there is sudden onset of the lesions without any warning or symptoms. When giving the history, the patient may appear unemotional, does not report pain, and denies self-infliction.¹  

In factitial purpura, the purple patches are clearly demarcated from uninvolved skin and have an unusual angular or geometric shape. The pattern typically takes the shape of the object used to create the purpura and lacks the features of recognizable dermatoses.² In our patient and those with similar linear purpuric streaks, we use the term penny purpura to indicate that the lesions resulted from rubbing with a penny or other blunt object, similar to coining. The lesions occur in areas that are easily accessible and visible such as the arms, chest, or chin. It is suggested that the child unconsciously wants the lesions to be seen. Histologic findings in factitial purpura include disruption of collagen fiber bundles and extravasated red blood cells in the dermis.³ Unfortunately, evolving lesions may give nonspecific histologic findings; when the clinical lesions are typical, skin biopsy usually is unnecessary and may be misleading. Laboratory test results such as complete blood cell count, prothrombin time, and partial thromboplastin time usually are within reference range, as in our patient. 

When evaluating these patients, confrontation is not recommended. More than two-thirds of affected patients have a history of trauma such as sexual/physical abuse or neglect, and the lesions typically arise during times of stress.^1,3 Thus, treatment includes nonaccusatory measures and referral for psychologic evaluation. The purpura will rapidly heal when covered with an occlusive dressing.²  

The differential diagnosis for penny purpura includes lesions that evolve from cupping and coining. Cupping is a type of complementary and alternative medicine that acts by correcting imbalances in the internal biofield and restoring the flow of qi, which determines the state of one's health and life span.⁴ Cupping is performed by placing a glass cup over a painful body part. A partial vacuum is created by flaming, mechanical withdrawal, or thermal cooling of the entrapped air under the cup. When the flame exhausts the supply of oxygen, the skin is sucked into the mouth of the glass, and the skin is bruised painlessly.⁴  

The differential also includes child maltreatment syndrome and other disorders that would potentiate bruising. Intravascular etiologies include idiopathic thrombocytopenic purpura, leukemia, coagulation disorders, and other causes of thrombocytopenia or platelet dysfunction.³ Extravascular etiologies include hereditary collagen vascular disease (eg, Ehlers-Danlos syndrome), malnutrition, and other disorders associated with a decrease in collagen and other tissues that support cutaneous vessels. Vascular etiologies include infectious (eg, Rocky Mountain spotted fever, meningococcemia) and noninfectious vasculitis (eg, Henoch-Schönlein purpura), leaky capillary syndrome, drug reactions, and other disorders associated with a loss of vascular integrity.³  

It is important to be able to differentiate self-inflicted lesions in a person who repeatedly acts as if he/she has a physical disorder from those that are created during the practices of cupping or any other cultural healing practice. Vascular disorders, malnutrition, and child abuse also should be excluded.³  

For our patient with factitial purpura, we gently encouraged the family to work with the child's pediatrician and a pediatric psychologist to deal with stress related to the recurrent rash and asked them to think of the rash as a result of an external cause; however, we were careful not to blame anyone for the rash.  

The Diagnosis: Factitial Purpura 

Factitial dermatologic disorders are characterized by skin findings triggered by deliberate manipulation of the skin with objects to create lesions and feign signs of a dermatologic condition to seek emotional and psychological benefit.¹ The etiology of the lesions is unclear, and the patient's history of the injury is hollow.² Most often, there is sudden onset of the lesions without any warning or symptoms. When giving the history, the patient may appear unemotional, does not report pain, and denies self-infliction.¹  

In factitial purpura, the purple patches are clearly demarcated from uninvolved skin and have an unusual angular or geometric shape. The pattern typically takes the shape of the object used to create the purpura and lacks the features of recognizable dermatoses.² In our patient and those with similar linear purpuric streaks, we use the term penny purpura to indicate that the lesions resulted from rubbing with a penny or other blunt object, similar to coining. The lesions occur in areas that are easily accessible and visible such as the arms, chest, or chin. It is suggested that the child unconsciously wants the lesions to be seen. Histologic findings in factitial purpura include disruption of collagen fiber bundles and extravasated red blood cells in the dermis.³ Unfortunately, evolving lesions may give nonspecific histologic findings; when the clinical lesions are typical, skin biopsy usually is unnecessary and may be misleading. Laboratory test results such as complete blood cell count, prothrombin time, and partial thromboplastin time usually are within reference range, as in our patient. 

When evaluating these patients, confrontation is not recommended. More than two-thirds of affected patients have a history of trauma such as sexual/physical abuse or neglect, and the lesions typically arise during times of stress.^1,3 Thus, treatment includes nonaccusatory measures and referral for psychologic evaluation. The purpura will rapidly heal when covered with an occlusive dressing.²  

The differential diagnosis for penny purpura includes lesions that evolve from cupping and coining. Cupping is a type of complementary and alternative medicine that acts by correcting imbalances in the internal biofield and restoring the flow of qi, which determines the state of one's health and life span.⁴ Cupping is performed by placing a glass cup over a painful body part. A partial vacuum is created by flaming, mechanical withdrawal, or thermal cooling of the entrapped air under the cup. When the flame exhausts the supply of oxygen, the skin is sucked into the mouth of the glass, and the skin is bruised painlessly.⁴  

The differential also includes child maltreatment syndrome and other disorders that would potentiate bruising. Intravascular etiologies include idiopathic thrombocytopenic purpura, leukemia, coagulation disorders, and other causes of thrombocytopenia or platelet dysfunction.³ Extravascular etiologies include hereditary collagen vascular disease (eg, Ehlers-Danlos syndrome), malnutrition, and other disorders associated with a decrease in collagen and other tissues that support cutaneous vessels. Vascular etiologies include infectious (eg, Rocky Mountain spotted fever, meningococcemia) and noninfectious vasculitis (eg, Henoch-Schönlein purpura), leaky capillary syndrome, drug reactions, and other disorders associated with a loss of vascular integrity.³  

It is important to be able to differentiate self-inflicted lesions in a person who repeatedly acts as if he/she has a physical disorder from those that are created during the practices of cupping or any other cultural healing practice. Vascular disorders, malnutrition, and child abuse also should be excluded.³  

For our patient with factitial purpura, we gently encouraged the family to work with the child's pediatrician and a pediatric psychologist to deal with stress related to the recurrent rash and asked them to think of the rash as a result of an external cause; however, we were careful not to blame anyone for the rash.  

The Diagnosis: Factitial Purpura 

Factitial dermatologic disorders are characterized by skin findings triggered by deliberate manipulation of the skin with objects to create lesions and feign signs of a dermatologic condition to seek emotional and psychological benefit.¹ The etiology of the lesions is unclear, and the patient's history of the injury is hollow.² Most often, there is sudden onset of the lesions without any warning or symptoms. When giving the history, the patient may appear unemotional, does not report pain, and denies self-infliction.¹  

In factitial purpura, the purple patches are clearly demarcated from uninvolved skin and have an unusual angular or geometric shape. The pattern typically takes the shape of the object used to create the purpura and lacks the features of recognizable dermatoses.² In our patient and those with similar linear purpuric streaks, we use the term penny purpura to indicate that the lesions resulted from rubbing with a penny or other blunt object, similar to coining. The lesions occur in areas that are easily accessible and visible such as the arms, chest, or chin. It is suggested that the child unconsciously wants the lesions to be seen. Histologic findings in factitial purpura include disruption of collagen fiber bundles and extravasated red blood cells in the dermis.³ Unfortunately, evolving lesions may give nonspecific histologic findings; when the clinical lesions are typical, skin biopsy usually is unnecessary and may be misleading. Laboratory test results such as complete blood cell count, prothrombin time, and partial thromboplastin time usually are within reference range, as in our patient. 

When evaluating these patients, confrontation is not recommended. More than two-thirds of affected patients have a history of trauma such as sexual/physical abuse or neglect, and the lesions typically arise during times of stress.^1,3 Thus, treatment includes nonaccusatory measures and referral for psychologic evaluation. The purpura will rapidly heal when covered with an occlusive dressing.²  

The differential diagnosis for penny purpura includes lesions that evolve from cupping and coining. Cupping is a type of complementary and alternative medicine that acts by correcting imbalances in the internal biofield and restoring the flow of qi, which determines the state of one's health and life span.⁴ Cupping is performed by placing a glass cup over a painful body part. A partial vacuum is created by flaming, mechanical withdrawal, or thermal cooling of the entrapped air under the cup. When the flame exhausts the supply of oxygen, the skin is sucked into the mouth of the glass, and the skin is bruised painlessly.⁴  

The differential also includes child maltreatment syndrome and other disorders that would potentiate bruising. Intravascular etiologies include idiopathic thrombocytopenic purpura, leukemia, coagulation disorders, and other causes of thrombocytopenia or platelet dysfunction.³ Extravascular etiologies include hereditary collagen vascular disease (eg, Ehlers-Danlos syndrome), malnutrition, and other disorders associated with a decrease in collagen and other tissues that support cutaneous vessels. Vascular etiologies include infectious (eg, Rocky Mountain spotted fever, meningococcemia) and noninfectious vasculitis (eg, Henoch-Schönlein purpura), leaky capillary syndrome, drug reactions, and other disorders associated with a loss of vascular integrity.³  

It is important to be able to differentiate self-inflicted lesions in a person who repeatedly acts as if he/she has a physical disorder from those that are created during the practices of cupping or any other cultural healing practice. Vascular disorders, malnutrition, and child abuse also should be excluded.³  

For our patient with factitial purpura, we gently encouraged the family to work with the child's pediatrician and a pediatric psychologist to deal with stress related to the recurrent rash and asked them to think of the rash as a result of an external cause; however, we were careful not to blame anyone for the rash.  

The Diagnosis: Cutaneous B-Cell Lymphoma, Follicle Center Subtype 

A 4-mm punch biopsy through the center of the largest lesion on the right posterior shoulder demonstrated a superficial and deep dermal atypical lymphoid infiltrate composed predominantly of small mature lymphocytes with interspersed intermediate-sized cells with irregular to cleaved nuclei, dispersed chromatin, one or more distinct nucleoli, occasional mitoses, and small amounts of cytoplasm (Figure, A). Immunoperoxidase studies showed the infiltrate to be a mixture of CD3+ T cells and CD20+ B cells (Figure, B). The B cells coexpressed B-cell lymphoma (Bcl) 6 protein (Figure, C) but were negative for multiple myeloma 1/interferon regulatory factor 4 and CD10; Bcl2 protein was positive in T cells but inconclusive for staining in B cells. Very few plasma cells were seen with CD138 stain. Fluorescence in situ hybridization studies were negative for IgH and BCL2 gene rearrangement. Molecular diagnostic studies for IgH and κ light chain gene rearrangement were positive for a clonal population. A clonal T-cell receptor γ chain gene rearrangement was not identified. The overall morphologic, immunophenotypic, and molecular findings were consistent with cutaneous involvement by a B-cell lymphoproliferative disorder, favoring primary cutaneous follicle center lymphoma (PCFCL). 

The patient was referred to our cancer center for further workup consisting of a complete blood cell count with differential; comprehensive metabolic panel; lactate dehydrogenase; serum protein electrophoresis; peripheral blood flow cytometry; and computed tomography of the chest, abdomen, and pelvis. The analysis was unremarkable, supporting primary cutaneous disease. Additional studies suggested in the National Comprehensive Cancer Network (NCCN) Guidelines for primary cutaneous B-cell lymphomas include hepatitis B testing if the patient is being considered for immunotherapy and/or chemotherapy due to risk of reactivation, pregnancy testing in women of childbearing age, and human immunodeficiency virus testing.¹ These tests were not performed in our patient because he did not have any risk factors for hepatitis B or human immunodeficiency virus. 

Primary cutaneous B-cell lymphomas originate in the skin without evidence of extracutaneous disease at presentation. They account for approximately 25% of primary cutaneous lymphomas in the United States, with primary cutaneous T-cell lymphoma being most common.² The revised 2017 World Health Organization classification system defines 3 major subtypes of primary cutaneous B-cell lymphoma (Table).^3-9 Primary cutaneous follicle center lymphoma is the most common subtype, accounting for approximately 60% of cases. In Europe, an association with Borrelia burgdorferi has been reported.¹⁰ The extent of skin involvement determines the T portion of TNM staging for PCFCL. It is based on the size and location of affected body regions that are delineated, such as the head and neck, chest, abdomen/genitalia, upper back, lower back/buttocks, each upper arm, each lower arm/hand, each upper leg, and each lower leg/foot. T1 is for solitary skin involvement in which the lesion is 5 cm or less in diameter (T1a) or greater than 5 cm (T1b). T2 is for regional skin involvement limited to 1 or 2 contiguous body regions, whereas T2a has all lesions confined to an area 15 cm or less in diameter, T2b has lesions confined to an area greater than 15 cm up to 30 cm in diameter, and the area for T2c is greater than 30 cm in diameter. Finally, T3 is generalized skin involvement, whereas T3a has multiple lesions in 2 noncontiguous body regions, and T3b has multiple lesions on 3 or more regions.¹¹ At presentation, our patient was considered T2cN0M0, as his lesions were present on only 2 contiguous regions extending beyond 30 cm without any evidence of lymph node involvement or metastasis.  

Treatment of PCFCL is tailored to each case, as there is a paucity of randomized data in this rare entity. It is guided by the number and location of cutaneous lesions, associated skin symptoms, age of the patient, and performance status. Local disease can be treated with intralesional corticosteroids, excision, or close monitoring if the patient is asymptomatic. Low-dose radiation therapy may be used as primary treatment or for local recurrence.¹² Patients with more extensive skin lesions can relapse after clearing; those with refractory disease can be managed with single-agent rituximab.¹³ Our patient underwent low-dose radiation therapy with good response and has not experienced recurrence. 

Lymphocytoma cutis, also known as benign reactive lymphoid hyperplasia, can be idiopathic or can arise after arthropod assault, penetrative skin trauma, drugs, or infections. In granuloma annulare, small dermal papules may present in isolation or coalesce to form annular plaques. It is a benign inflammatory disorder of unknown cause, can have mild pruritus, and usually is self-limited. Pyogenic granuloma is a benign vascular proliferation of unknown etiology. Sarcoidosis is an immune-mediated systemic disorder with granuloma formation that has a predilection for the lungs and the skin. 

The Diagnosis: Cutaneous B-Cell Lymphoma, Follicle Center Subtype 

A 4-mm punch biopsy through the center of the largest lesion on the right posterior shoulder demonstrated a superficial and deep dermal atypical lymphoid infiltrate composed predominantly of small mature lymphocytes with interspersed intermediate-sized cells with irregular to cleaved nuclei, dispersed chromatin, one or more distinct nucleoli, occasional mitoses, and small amounts of cytoplasm (Figure, A). Immunoperoxidase studies showed the infiltrate to be a mixture of CD3+ T cells and CD20+ B cells (Figure, B). The B cells coexpressed B-cell lymphoma (Bcl) 6 protein (Figure, C) but were negative for multiple myeloma 1/interferon regulatory factor 4 and CD10; Bcl2 protein was positive in T cells but inconclusive for staining in B cells. Very few plasma cells were seen with CD138 stain. Fluorescence in situ hybridization studies were negative for IgH and BCL2 gene rearrangement. Molecular diagnostic studies for IgH and κ light chain gene rearrangement were positive for a clonal population. A clonal T-cell receptor γ chain gene rearrangement was not identified. The overall morphologic, immunophenotypic, and molecular findings were consistent with cutaneous involvement by a B-cell lymphoproliferative disorder, favoring primary cutaneous follicle center lymphoma (PCFCL). 

The patient was referred to our cancer center for further workup consisting of a complete blood cell count with differential; comprehensive metabolic panel; lactate dehydrogenase; serum protein electrophoresis; peripheral blood flow cytometry; and computed tomography of the chest, abdomen, and pelvis. The analysis was unremarkable, supporting primary cutaneous disease. Additional studies suggested in the National Comprehensive Cancer Network (NCCN) Guidelines for primary cutaneous B-cell lymphomas include hepatitis B testing if the patient is being considered for immunotherapy and/or chemotherapy due to risk of reactivation, pregnancy testing in women of childbearing age, and human immunodeficiency virus testing.¹ These tests were not performed in our patient because he did not have any risk factors for hepatitis B or human immunodeficiency virus. 

Primary cutaneous B-cell lymphomas originate in the skin without evidence of extracutaneous disease at presentation. They account for approximately 25% of primary cutaneous lymphomas in the United States, with primary cutaneous T-cell lymphoma being most common.² The revised 2017 World Health Organization classification system defines 3 major subtypes of primary cutaneous B-cell lymphoma (Table).^3-9 Primary cutaneous follicle center lymphoma is the most common subtype, accounting for approximately 60% of cases. In Europe, an association with Borrelia burgdorferi has been reported.¹⁰ The extent of skin involvement determines the T portion of TNM staging for PCFCL. It is based on the size and location of affected body regions that are delineated, such as the head and neck, chest, abdomen/genitalia, upper back, lower back/buttocks, each upper arm, each lower arm/hand, each upper leg, and each lower leg/foot. T1 is for solitary skin involvement in which the lesion is 5 cm or less in diameter (T1a) or greater than 5 cm (T1b). T2 is for regional skin involvement limited to 1 or 2 contiguous body regions, whereas T2a has all lesions confined to an area 15 cm or less in diameter, T2b has lesions confined to an area greater than 15 cm up to 30 cm in diameter, and the area for T2c is greater than 30 cm in diameter. Finally, T3 is generalized skin involvement, whereas T3a has multiple lesions in 2 noncontiguous body regions, and T3b has multiple lesions on 3 or more regions.¹¹ At presentation, our patient was considered T2cN0M0, as his lesions were present on only 2 contiguous regions extending beyond 30 cm without any evidence of lymph node involvement or metastasis.  

Treatment of PCFCL is tailored to each case, as there is a paucity of randomized data in this rare entity. It is guided by the number and location of cutaneous lesions, associated skin symptoms, age of the patient, and performance status. Local disease can be treated with intralesional corticosteroids, excision, or close monitoring if the patient is asymptomatic. Low-dose radiation therapy may be used as primary treatment or for local recurrence.¹² Patients with more extensive skin lesions can relapse after clearing; those with refractory disease can be managed with single-agent rituximab.¹³ Our patient underwent low-dose radiation therapy with good response and has not experienced recurrence. 

Lymphocytoma cutis, also known as benign reactive lymphoid hyperplasia, can be idiopathic or can arise after arthropod assault, penetrative skin trauma, drugs, or infections. In granuloma annulare, small dermal papules may present in isolation or coalesce to form annular plaques. It is a benign inflammatory disorder of unknown cause, can have mild pruritus, and usually is self-limited. Pyogenic granuloma is a benign vascular proliferation of unknown etiology. Sarcoidosis is an immune-mediated systemic disorder with granuloma formation that has a predilection for the lungs and the skin. 

The Diagnosis: Cutaneous B-Cell Lymphoma, Follicle Center Subtype 

A 4-mm punch biopsy through the center of the largest lesion on the right posterior shoulder demonstrated a superficial and deep dermal atypical lymphoid infiltrate composed predominantly of small mature lymphocytes with interspersed intermediate-sized cells with irregular to cleaved nuclei, dispersed chromatin, one or more distinct nucleoli, occasional mitoses, and small amounts of cytoplasm (Figure, A). Immunoperoxidase studies showed the infiltrate to be a mixture of CD3+ T cells and CD20+ B cells (Figure, B). The B cells coexpressed B-cell lymphoma (Bcl) 6 protein (Figure, C) but were negative for multiple myeloma 1/interferon regulatory factor 4 and CD10; Bcl2 protein was positive in T cells but inconclusive for staining in B cells. Very few plasma cells were seen with CD138 stain. Fluorescence in situ hybridization studies were negative for IgH and BCL2 gene rearrangement. Molecular diagnostic studies for IgH and κ light chain gene rearrangement were positive for a clonal population. A clonal T-cell receptor γ chain gene rearrangement was not identified. The overall morphologic, immunophenotypic, and molecular findings were consistent with cutaneous involvement by a B-cell lymphoproliferative disorder, favoring primary cutaneous follicle center lymphoma (PCFCL). 

The patient was referred to our cancer center for further workup consisting of a complete blood cell count with differential; comprehensive metabolic panel; lactate dehydrogenase; serum protein electrophoresis; peripheral blood flow cytometry; and computed tomography of the chest, abdomen, and pelvis. The analysis was unremarkable, supporting primary cutaneous disease. Additional studies suggested in the National Comprehensive Cancer Network (NCCN) Guidelines for primary cutaneous B-cell lymphomas include hepatitis B testing if the patient is being considered for immunotherapy and/or chemotherapy due to risk of reactivation, pregnancy testing in women of childbearing age, and human immunodeficiency virus testing.¹ These tests were not performed in our patient because he did not have any risk factors for hepatitis B or human immunodeficiency virus. 

Primary cutaneous B-cell lymphomas originate in the skin without evidence of extracutaneous disease at presentation. They account for approximately 25% of primary cutaneous lymphomas in the United States, with primary cutaneous T-cell lymphoma being most common.² The revised 2017 World Health Organization classification system defines 3 major subtypes of primary cutaneous B-cell lymphoma (Table).^3-9 Primary cutaneous follicle center lymphoma is the most common subtype, accounting for approximately 60% of cases. In Europe, an association with Borrelia burgdorferi has been reported.¹⁰ The extent of skin involvement determines the T portion of TNM staging for PCFCL. It is based on the size and location of affected body regions that are delineated, such as the head and neck, chest, abdomen/genitalia, upper back, lower back/buttocks, each upper arm, each lower arm/hand, each upper leg, and each lower leg/foot. T1 is for solitary skin involvement in which the lesion is 5 cm or less in diameter (T1a) or greater than 5 cm (T1b). T2 is for regional skin involvement limited to 1 or 2 contiguous body regions, whereas T2a has all lesions confined to an area 15 cm or less in diameter, T2b has lesions confined to an area greater than 15 cm up to 30 cm in diameter, and the area for T2c is greater than 30 cm in diameter. Finally, T3 is generalized skin involvement, whereas T3a has multiple lesions in 2 noncontiguous body regions, and T3b has multiple lesions on 3 or more regions.¹¹ At presentation, our patient was considered T2cN0M0, as his lesions were present on only 2 contiguous regions extending beyond 30 cm without any evidence of lymph node involvement or metastasis.  

Treatment of PCFCL is tailored to each case, as there is a paucity of randomized data in this rare entity. It is guided by the number and location of cutaneous lesions, associated skin symptoms, age of the patient, and performance status. Local disease can be treated with intralesional corticosteroids, excision, or close monitoring if the patient is asymptomatic. Low-dose radiation therapy may be used as primary treatment or for local recurrence.¹² Patients with more extensive skin lesions can relapse after clearing; those with refractory disease can be managed with single-agent rituximab.¹³ Our patient underwent low-dose radiation therapy with good response and has not experienced recurrence. 

Lymphocytoma cutis, also known as benign reactive lymphoid hyperplasia, can be idiopathic or can arise after arthropod assault, penetrative skin trauma, drugs, or infections. In granuloma annulare, small dermal papules may present in isolation or coalesce to form annular plaques. It is a benign inflammatory disorder of unknown cause, can have mild pruritus, and usually is self-limited. Pyogenic granuloma is a benign vascular proliferation of unknown etiology. Sarcoidosis is an immune-mediated systemic disorder with granuloma formation that has a predilection for the lungs and the skin. 

The Diagnosis: Atypical Fibroxanthoma  

Shave biopsy showed the superficial aspect of a highly cellular tumor composed of pleomorphic spindle cells exhibiting storiform growth and increased mitotic activity (Figure 1). The tumor stained positive for factor XIIIa, CD163, CD68, and smooth muscle actin (mild), and negative for high-molecular-weight cytokeratin (HMW-CK), p63, S-100, and melan-A. Subsequent excision with 0.5-cm margins was performed, and histopathology showed a well-circumscribed tumor contained within the dermis with a histologic scar at the outer margin (Figure 2). There was no lymphovascular or perineural invasion by tumor cells. Re-excision with 0.3-cm margins demonstrated no residual scar or tumor, and external radiation was deferred due to clear surgical margins.  

Atypical fibroxanthoma (AFX) belongs to a group of spindle cell neoplasms that can be diagnostically challenging, as they often lack specific morphologic features on examination or routine histology. These neoplasms--of which the differential includes malignant fibrous histiocytoma, spindle cell squamous cell carcinoma (SCC), desmoplastic melanoma, and leiomyosarcoma--may each appear as a rapidly enlarging solitary plaque or nodule on sun-damaged skin on the head and neck or less commonly on the trunk, arms, or legs. Histologically, the cells of AFX exhibit notable pleomorphism with frequent atypical mitotic figures and nonspecific surrounding dermal changes. Subcutaneous and lymphovascular or perineural invasion of tumor cells can point away from the diagnosis of AFX; however, these features are likely to be missed in small superficial shave biopsies.^1,2 Therefore, immunohistochemistry (IHC) and adequate tumor sampling are essential in the accurate diagnosis of AFX and other spindle cell neoplasms.  

Several IHC markers have been employed in differentiating AFX from other spindle cell neoplasms.^3-8 Positive stains for AFX include factor XIIIa (10%-25%), vimentin (>99%), CD10 (95%-100%), procollagen (87%), CD99 (35%-73%), CD163 (37%-79%), smooth muscle actin (50%), CD68 (>50%), and CD31 (43%). Other stains, such as HMW-CK, S-100, p63, desmin, CD34, and melan-A, typically are negative in AFX but are actively expressed in other pleomorphic spindle cell tumors. The Table summarizes the utility of these various markers in narrowing the differential diagnosis of a spindle cell lesion. Selection of an appropriate panel of IHC markers is critical for accurate diagnosis of AFX and exclusion of more aggressive, poorly differentiated spindle cell neoplasms. Key IHC markers include S-100 (negative in AFX; positive in desmoplastic melanoma), HMW-CK (negative in AFX; positive in spindle cell SCC), and p63 (negative in AFX; positive in spindle cell SCC). Benoit et al⁹ reported a case of a poorly differentiated spindle cell SCC misdiagnosed as AFX based on a limited IHC panel that was negative for pancytokeratin and S-100. Later, a more comprehensive IHC panel including HMW-CK and p63 confirmed spindle cell SCC, but by this time, a delay in therapy had allowed the tumor to metastasize, which ultimately proved fatal to the patient.⁹  

In addition to incomplete IHC evaluation, accurate diagnosis of spindle cell tumors also may be obscured by inadequate tumor sampling. The cells of AFX tumors often are well circumscribed and dermally based, and an excisional biopsy is the preferred biopsy procedure for AFX. A tumor invading into subcutaneous tissue or into lymphovascular or perineural structures suggests a more aggressive, poorly differentiated spindle cell neoplasm.^1,3 For example, the tumor cells of malignant fibrous histiocytoma, which belongs to the undifferentiated pleomorphic sarcoma group, may appear identical to those of AFX on histology, and the 2 tumors display similar IHC profiles.³ Malignant fibrous histiocytoma, however, extends into the subcutaneous space and portends a notably worse prognosis compared to AFX. Malignant fibrous histiocytoma tumors therefore require more aggressive treatment strategies such as external beam radiation therapy, whereas AFX can be safely treated with surgical removal alone. In our patient, complete visualization of tumor margins solidified the diagnosis of AFX and spared our patient from unnecessary radiation therapy. Overall, AFX has a good prognosis and metastasis is rare, particularly when good margin control is achieved.¹⁰ 

Our case highlights the importance of clinicopathologic correlation, including appropriate IHC analysis and adequate tumor sampling in the diagnostic workup of a pleomorphic spindle cell neoplasm. Although these tumors are well studied, their notable degree of clinical and histologic heterogeneity may pose a diagnostic challenge to even experienced dermatologists and require careful consideration of the potential pitfalls in diagnosis.  

The Diagnosis: Atypical Fibroxanthoma  

Shave biopsy showed the superficial aspect of a highly cellular tumor composed of pleomorphic spindle cells exhibiting storiform growth and increased mitotic activity (Figure 1). The tumor stained positive for factor XIIIa, CD163, CD68, and smooth muscle actin (mild), and negative for high-molecular-weight cytokeratin (HMW-CK), p63, S-100, and melan-A. Subsequent excision with 0.5-cm margins was performed, and histopathology showed a well-circumscribed tumor contained within the dermis with a histologic scar at the outer margin (Figure 2). There was no lymphovascular or perineural invasion by tumor cells. Re-excision with 0.3-cm margins demonstrated no residual scar or tumor, and external radiation was deferred due to clear surgical margins.  

Atypical fibroxanthoma (AFX) belongs to a group of spindle cell neoplasms that can be diagnostically challenging, as they often lack specific morphologic features on examination or routine histology. These neoplasms--of which the differential includes malignant fibrous histiocytoma, spindle cell squamous cell carcinoma (SCC), desmoplastic melanoma, and leiomyosarcoma--may each appear as a rapidly enlarging solitary plaque or nodule on sun-damaged skin on the head and neck or less commonly on the trunk, arms, or legs. Histologically, the cells of AFX exhibit notable pleomorphism with frequent atypical mitotic figures and nonspecific surrounding dermal changes. Subcutaneous and lymphovascular or perineural invasion of tumor cells can point away from the diagnosis of AFX; however, these features are likely to be missed in small superficial shave biopsies.^1,2 Therefore, immunohistochemistry (IHC) and adequate tumor sampling are essential in the accurate diagnosis of AFX and other spindle cell neoplasms.  

Several IHC markers have been employed in differentiating AFX from other spindle cell neoplasms.^3-8 Positive stains for AFX include factor XIIIa (10%-25%), vimentin (>99%), CD10 (95%-100%), procollagen (87%), CD99 (35%-73%), CD163 (37%-79%), smooth muscle actin (50%), CD68 (>50%), and CD31 (43%). Other stains, such as HMW-CK, S-100, p63, desmin, CD34, and melan-A, typically are negative in AFX but are actively expressed in other pleomorphic spindle cell tumors. The Table summarizes the utility of these various markers in narrowing the differential diagnosis of a spindle cell lesion. Selection of an appropriate panel of IHC markers is critical for accurate diagnosis of AFX and exclusion of more aggressive, poorly differentiated spindle cell neoplasms. Key IHC markers include S-100 (negative in AFX; positive in desmoplastic melanoma), HMW-CK (negative in AFX; positive in spindle cell SCC), and p63 (negative in AFX; positive in spindle cell SCC). Benoit et al⁹ reported a case of a poorly differentiated spindle cell SCC misdiagnosed as AFX based on a limited IHC panel that was negative for pancytokeratin and S-100. Later, a more comprehensive IHC panel including HMW-CK and p63 confirmed spindle cell SCC, but by this time, a delay in therapy had allowed the tumor to metastasize, which ultimately proved fatal to the patient.⁹  

In addition to incomplete IHC evaluation, accurate diagnosis of spindle cell tumors also may be obscured by inadequate tumor sampling. The cells of AFX tumors often are well circumscribed and dermally based, and an excisional biopsy is the preferred biopsy procedure for AFX. A tumor invading into subcutaneous tissue or into lymphovascular or perineural structures suggests a more aggressive, poorly differentiated spindle cell neoplasm.^1,3 For example, the tumor cells of malignant fibrous histiocytoma, which belongs to the undifferentiated pleomorphic sarcoma group, may appear identical to those of AFX on histology, and the 2 tumors display similar IHC profiles.³ Malignant fibrous histiocytoma, however, extends into the subcutaneous space and portends a notably worse prognosis compared to AFX. Malignant fibrous histiocytoma tumors therefore require more aggressive treatment strategies such as external beam radiation therapy, whereas AFX can be safely treated with surgical removal alone. In our patient, complete visualization of tumor margins solidified the diagnosis of AFX and spared our patient from unnecessary radiation therapy. Overall, AFX has a good prognosis and metastasis is rare, particularly when good margin control is achieved.¹⁰ 

Our case highlights the importance of clinicopathologic correlation, including appropriate IHC analysis and adequate tumor sampling in the diagnostic workup of a pleomorphic spindle cell neoplasm. Although these tumors are well studied, their notable degree of clinical and histologic heterogeneity may pose a diagnostic challenge to even experienced dermatologists and require careful consideration of the potential pitfalls in diagnosis.  

The Diagnosis: Atypical Fibroxanthoma  

Shave biopsy showed the superficial aspect of a highly cellular tumor composed of pleomorphic spindle cells exhibiting storiform growth and increased mitotic activity (Figure 1). The tumor stained positive for factor XIIIa, CD163, CD68, and smooth muscle actin (mild), and negative for high-molecular-weight cytokeratin (HMW-CK), p63, S-100, and melan-A. Subsequent excision with 0.5-cm margins was performed, and histopathology showed a well-circumscribed tumor contained within the dermis with a histologic scar at the outer margin (Figure 2). There was no lymphovascular or perineural invasion by tumor cells. Re-excision with 0.3-cm margins demonstrated no residual scar or tumor, and external radiation was deferred due to clear surgical margins.  

Atypical fibroxanthoma (AFX) belongs to a group of spindle cell neoplasms that can be diagnostically challenging, as they often lack specific morphologic features on examination or routine histology. These neoplasms--of which the differential includes malignant fibrous histiocytoma, spindle cell squamous cell carcinoma (SCC), desmoplastic melanoma, and leiomyosarcoma--may each appear as a rapidly enlarging solitary plaque or nodule on sun-damaged skin on the head and neck or less commonly on the trunk, arms, or legs. Histologically, the cells of AFX exhibit notable pleomorphism with frequent atypical mitotic figures and nonspecific surrounding dermal changes. Subcutaneous and lymphovascular or perineural invasion of tumor cells can point away from the diagnosis of AFX; however, these features are likely to be missed in small superficial shave biopsies.^1,2 Therefore, immunohistochemistry (IHC) and adequate tumor sampling are essential in the accurate diagnosis of AFX and other spindle cell neoplasms.  

Several IHC markers have been employed in differentiating AFX from other spindle cell neoplasms.^3-8 Positive stains for AFX include factor XIIIa (10%-25%), vimentin (>99%), CD10 (95%-100%), procollagen (87%), CD99 (35%-73%), CD163 (37%-79%), smooth muscle actin (50%), CD68 (>50%), and CD31 (43%). Other stains, such as HMW-CK, S-100, p63, desmin, CD34, and melan-A, typically are negative in AFX but are actively expressed in other pleomorphic spindle cell tumors. The Table summarizes the utility of these various markers in narrowing the differential diagnosis of a spindle cell lesion. Selection of an appropriate panel of IHC markers is critical for accurate diagnosis of AFX and exclusion of more aggressive, poorly differentiated spindle cell neoplasms. Key IHC markers include S-100 (negative in AFX; positive in desmoplastic melanoma), HMW-CK (negative in AFX; positive in spindle cell SCC), and p63 (negative in AFX; positive in spindle cell SCC). Benoit et al⁹ reported a case of a poorly differentiated spindle cell SCC misdiagnosed as AFX based on a limited IHC panel that was negative for pancytokeratin and S-100. Later, a more comprehensive IHC panel including HMW-CK and p63 confirmed spindle cell SCC, but by this time, a delay in therapy had allowed the tumor to metastasize, which ultimately proved fatal to the patient.⁹  

In addition to incomplete IHC evaluation, accurate diagnosis of spindle cell tumors also may be obscured by inadequate tumor sampling. The cells of AFX tumors often are well circumscribed and dermally based, and an excisional biopsy is the preferred biopsy procedure for AFX. A tumor invading into subcutaneous tissue or into lymphovascular or perineural structures suggests a more aggressive, poorly differentiated spindle cell neoplasm.^1,3 For example, the tumor cells of malignant fibrous histiocytoma, which belongs to the undifferentiated pleomorphic sarcoma group, may appear identical to those of AFX on histology, and the 2 tumors display similar IHC profiles.³ Malignant fibrous histiocytoma, however, extends into the subcutaneous space and portends a notably worse prognosis compared to AFX. Malignant fibrous histiocytoma tumors therefore require more aggressive treatment strategies such as external beam radiation therapy, whereas AFX can be safely treated with surgical removal alone. In our patient, complete visualization of tumor margins solidified the diagnosis of AFX and spared our patient from unnecessary radiation therapy. Overall, AFX has a good prognosis and metastasis is rare, particularly when good margin control is achieved.¹⁰ 

Our case highlights the importance of clinicopathologic correlation, including appropriate IHC analysis and adequate tumor sampling in the diagnostic workup of a pleomorphic spindle cell neoplasm. Although these tumors are well studied, their notable degree of clinical and histologic heterogeneity may pose a diagnostic challenge to even experienced dermatologists and require careful consideration of the potential pitfalls in diagnosis.  

The Diagnosis: Wells Syndrome 

Histopathologic examination of the biopsy demonstrated overlying acanthosis, focal spongiosis, and exocytosis. There also was proliferation and thickening of superficial capillaries and papillary fibrosis (Figure, A). There was a mixed interstitial and perivascular inflammatory infiltrate consisting of lymphocytes, histiocytes, plasma cells, and eosinophils (Figure, A and B). Occasional flame figures were identified (Figure, C). 

Wells syndrome, also known as eosinophilic cellulitis, was first described in 1971 by Wells¹ as a recurrent granulomatous dermatitis with eosinophilia. Rarely reported worldwide, this chronic relapsing condition is characterized by a pronounced eosinophilic infiltrate of the dermis resembling urticaria or cellulitis.² The exact etiology has not been elucidated; however, links to certain medications, vaccines, exaggerated arthropod reactions, infections, and malignancies have been documented.³  

Wells syndrome is a diagnosis of exclusion and lacks a predictable dermatologic presentation, thereby mandating focused clinical follow-up as well as correlation with histopathology findings. Although the classic histologic hallmark of Wells syndrome is scattered flame figures, this finding is not specific and can be found in other hypereosinophilic conditions.² Clinical manifestations most often consist of 2 distinct phases: an initial painful burning or pruritic sensation, followed by the development of erythematous and edematous dermal plaques that may heal with slight hyperpigmentation over 4 to 8 weeks. A case series of 19 patients demonstrated variants of Wells syndrome, with an annular granuloma-like appearance found primarily in adults and the signature plaque-type appearance predominating in children.⁴  

Acute urticaria is characterized by pruritic erythematous wheals secondary to a histamine-mediated response brought on by a variety of triggers, typically allergic and self-resolving within 24 hours. When such lesions last longer than 24 hours, biopsy should be performed to exclude urticarial vasculitis, which is characterized by a burning or painful sensation rather than pruritis, in addition to dermal neutrophilia and perivascular infiltrate on histology. Erythema migrans of Lyme disease begins at the site of a tick bite, evolving from a red macule to an expanding targetoid lesion and typically is not pruritic. Infectious cellulitis presents with warm, tender, and poorly defined erythematous patches; can progress rapidly; and is accompanied by systemic symptoms such as fevers, malaise, and lymphadenopathy.  

Best evidence favors the use of moderate- to high-dose corticosteroids as first-line treatment.⁵ The use of tumor necrosis factor blockers, various immunomodulating agents, and combination therapy with levocetirizine and hydroxyzine have demonstrated variable levels of efficacy, albeit often followed by high rates of relapse with drug discontinuation.⁶  

The Diagnosis: Wells Syndrome 

Histopathologic examination of the biopsy demonstrated overlying acanthosis, focal spongiosis, and exocytosis. There also was proliferation and thickening of superficial capillaries and papillary fibrosis (Figure, A). There was a mixed interstitial and perivascular inflammatory infiltrate consisting of lymphocytes, histiocytes, plasma cells, and eosinophils (Figure, A and B). Occasional flame figures were identified (Figure, C). 

Wells syndrome, also known as eosinophilic cellulitis, was first described in 1971 by Wells¹ as a recurrent granulomatous dermatitis with eosinophilia. Rarely reported worldwide, this chronic relapsing condition is characterized by a pronounced eosinophilic infiltrate of the dermis resembling urticaria or cellulitis.² The exact etiology has not been elucidated; however, links to certain medications, vaccines, exaggerated arthropod reactions, infections, and malignancies have been documented.³  

Wells syndrome is a diagnosis of exclusion and lacks a predictable dermatologic presentation, thereby mandating focused clinical follow-up as well as correlation with histopathology findings. Although the classic histologic hallmark of Wells syndrome is scattered flame figures, this finding is not specific and can be found in other hypereosinophilic conditions.² Clinical manifestations most often consist of 2 distinct phases: an initial painful burning or pruritic sensation, followed by the development of erythematous and edematous dermal plaques that may heal with slight hyperpigmentation over 4 to 8 weeks. A case series of 19 patients demonstrated variants of Wells syndrome, with an annular granuloma-like appearance found primarily in adults and the signature plaque-type appearance predominating in children.⁴  

Acute urticaria is characterized by pruritic erythematous wheals secondary to a histamine-mediated response brought on by a variety of triggers, typically allergic and self-resolving within 24 hours. When such lesions last longer than 24 hours, biopsy should be performed to exclude urticarial vasculitis, which is characterized by a burning or painful sensation rather than pruritis, in addition to dermal neutrophilia and perivascular infiltrate on histology. Erythema migrans of Lyme disease begins at the site of a tick bite, evolving from a red macule to an expanding targetoid lesion and typically is not pruritic. Infectious cellulitis presents with warm, tender, and poorly defined erythematous patches; can progress rapidly; and is accompanied by systemic symptoms such as fevers, malaise, and lymphadenopathy.  

Best evidence favors the use of moderate- to high-dose corticosteroids as first-line treatment.⁵ The use of tumor necrosis factor blockers, various immunomodulating agents, and combination therapy with levocetirizine and hydroxyzine have demonstrated variable levels of efficacy, albeit often followed by high rates of relapse with drug discontinuation.⁶  

The Diagnosis: Wells Syndrome 

Histopathologic examination of the biopsy demonstrated overlying acanthosis, focal spongiosis, and exocytosis. There also was proliferation and thickening of superficial capillaries and papillary fibrosis (Figure, A). There was a mixed interstitial and perivascular inflammatory infiltrate consisting of lymphocytes, histiocytes, plasma cells, and eosinophils (Figure, A and B). Occasional flame figures were identified (Figure, C). 

Wells syndrome, also known as eosinophilic cellulitis, was first described in 1971 by Wells¹ as a recurrent granulomatous dermatitis with eosinophilia. Rarely reported worldwide, this chronic relapsing condition is characterized by a pronounced eosinophilic infiltrate of the dermis resembling urticaria or cellulitis.² The exact etiology has not been elucidated; however, links to certain medications, vaccines, exaggerated arthropod reactions, infections, and malignancies have been documented.³  

Wells syndrome is a diagnosis of exclusion and lacks a predictable dermatologic presentation, thereby mandating focused clinical follow-up as well as correlation with histopathology findings. Although the classic histologic hallmark of Wells syndrome is scattered flame figures, this finding is not specific and can be found in other hypereosinophilic conditions.² Clinical manifestations most often consist of 2 distinct phases: an initial painful burning or pruritic sensation, followed by the development of erythematous and edematous dermal plaques that may heal with slight hyperpigmentation over 4 to 8 weeks. A case series of 19 patients demonstrated variants of Wells syndrome, with an annular granuloma-like appearance found primarily in adults and the signature plaque-type appearance predominating in children.⁴  

Acute urticaria is characterized by pruritic erythematous wheals secondary to a histamine-mediated response brought on by a variety of triggers, typically allergic and self-resolving within 24 hours. When such lesions last longer than 24 hours, biopsy should be performed to exclude urticarial vasculitis, which is characterized by a burning or painful sensation rather than pruritis, in addition to dermal neutrophilia and perivascular infiltrate on histology. Erythema migrans of Lyme disease begins at the site of a tick bite, evolving from a red macule to an expanding targetoid lesion and typically is not pruritic. Infectious cellulitis presents with warm, tender, and poorly defined erythematous patches; can progress rapidly; and is accompanied by systemic symptoms such as fevers, malaise, and lymphadenopathy.  

Best evidence favors the use of moderate- to high-dose corticosteroids as first-line treatment.⁵ The use of tumor necrosis factor blockers, various immunomodulating agents, and combination therapy with levocetirizine and hydroxyzine have demonstrated variable levels of efficacy, albeit often followed by high rates of relapse with drug discontinuation.⁶  

The Diagnosis: B-Cell Acute Lymphoblastic Leukemia 

A 4-mm punch biopsy of one of the scalp lesions showed a diffuse infiltrate of intermediately sized cells with variably mature chromatin and irregular nuclear contours, consistent with a neoplastic process. Numerous mitotic figures were present, indicating a high proliferation rate (Figure 1). At that time there was no evidence of systemic involvement. A repeat biopsy with concurrent bone marrow biopsy was scheduled 10 days after the patient's initial presentation for further classification. Laboratory studies at that time revealed leukocytosis with elevated neutrophils and lymphocytes as well as a high absolute blast count. 

On immunohistochemical staining, the neoplastic cells were positive for CD45, which indicated the neoplasm was hematopoietic, as well as CD10 and the B-cell antigens PAX-5 and CD79a. The cells were negative for CD20, which also is a B-cell marker, but this marker is only expressed in approximately half of pediatric acute lymphoblastic leukemia (ALL) cases with B-cell precursor origin.¹ Markers that typically are expressed in B-cell acute lymphoblastic leukemia (B-ALL)--CD34 and terminal deoxynucleotidyl transferase--were both negative. These results were somewhat contradictory, and the differential remained open to both B-ALL and mature B-cell lymphoma. A bone marrow biopsy showed approximately 65% blasts or leukemic cells (Figure 2). Flow cytometry showed the cells were positive for CD10, CD19, weak CD79a, and variable lambda surface antigen expression. The cells were negative for expression of CD20, CD34, terminal deoxynucleotidyl transferase, myeloid antigens, and CD3. Ultimately, the morphology and immunophenotype were most consistent with a diagnosis of B-ALL. Fluorescence in situ hybridization revealed mixed lineage leukemia, MLL, gene rearrangements.  

Potential oncologic processes include leukemia cutis, lymphoblastic leukemia/lymphoma, Langerhans cell histiocytosis, and rhabdomyosarcoma. Initial laboratory test results were reassuring. Infectious processes in the differential include deep fungal infections such as coccidioidomycosis and nontuberculous mycobacterial infections. Coccidioidomycosis was the most likely to cause skin lesions or masses in our patient; however, it was considered less likely because the patient's family had not traveled or been exposed to an endemic area.³  

Benign tumors in the differential include deep hemangioma, which was deemed less likely in our patient because most hemangiomas reach 80% of their maximum size by 5 months of age.⁴ Another possible benign tumor is infantile myofibromatosis, which is rare but is the most common fibrous tumor of infancy.⁵  

Early-onset childhood sarcoidosis also has been shown to produce multiple nontender firm nodules.² This process was considered unlikely in our patient because not only is the disease relatively rare in the pediatric population, but most reported childhood cases have occurred in patients aged 13 to 15 years.⁶ Additionally, no uveitis or arthritis was observed in this case. 

Ultimately, histopathology and bone marrow biopsy were necessary to determine the diagnosis of B-ALL. Although uncommon, cutaneous involvement can be an early sign of ALL in children.⁷ Thus, neoplastic etiologies should be considered in the workup of cutaneous nodules in children, especially when these nodules are hard, rapidly growing, ulcerated, fixed, and/or vascular.⁸ Once the diagnosis is established, initial workup of ALL in children should include complete blood cell count with manual differential, prothrombin time, partial thromboplastin time, electrolytes, uric acid, and renal and liver function tests. Often, baseline viral titers such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, and varicella-zoster virus also are included. Patients are risk stratified to the appropriate level of treatment based on tumor immunophenotype, cytogenetic findings, patient age, white blood cell count at the time of diagnosis, and response to initial therapy. Treatment typically is comprised of a multidrug regimen divided into several phases--induction, consolidation, and maintenance--as well as therapy directed to the central nervous system. Treatment protocols usually take 2 to 3 years to complete.  

Our patient was treated with 1 dose of intrathecal methotrexate before starting the Interfant-06 protocol with a 7-day methylprednisolone prophase. The patient's nodules shrank over time and were no longer present after 14 days of treatment. 

The Diagnosis: B-Cell Acute Lymphoblastic Leukemia 

A 4-mm punch biopsy of one of the scalp lesions showed a diffuse infiltrate of intermediately sized cells with variably mature chromatin and irregular nuclear contours, consistent with a neoplastic process. Numerous mitotic figures were present, indicating a high proliferation rate (Figure 1). At that time there was no evidence of systemic involvement. A repeat biopsy with concurrent bone marrow biopsy was scheduled 10 days after the patient's initial presentation for further classification. Laboratory studies at that time revealed leukocytosis with elevated neutrophils and lymphocytes as well as a high absolute blast count. 

On immunohistochemical staining, the neoplastic cells were positive for CD45, which indicated the neoplasm was hematopoietic, as well as CD10 and the B-cell antigens PAX-5 and CD79a. The cells were negative for CD20, which also is a B-cell marker, but this marker is only expressed in approximately half of pediatric acute lymphoblastic leukemia (ALL) cases with B-cell precursor origin.¹ Markers that typically are expressed in B-cell acute lymphoblastic leukemia (B-ALL)--CD34 and terminal deoxynucleotidyl transferase--were both negative. These results were somewhat contradictory, and the differential remained open to both B-ALL and mature B-cell lymphoma. A bone marrow biopsy showed approximately 65% blasts or leukemic cells (Figure 2). Flow cytometry showed the cells were positive for CD10, CD19, weak CD79a, and variable lambda surface antigen expression. The cells were negative for expression of CD20, CD34, terminal deoxynucleotidyl transferase, myeloid antigens, and CD3. Ultimately, the morphology and immunophenotype were most consistent with a diagnosis of B-ALL. Fluorescence in situ hybridization revealed mixed lineage leukemia, MLL, gene rearrangements.  

Potential oncologic processes include leukemia cutis, lymphoblastic leukemia/lymphoma, Langerhans cell histiocytosis, and rhabdomyosarcoma. Initial laboratory test results were reassuring. Infectious processes in the differential include deep fungal infections such as coccidioidomycosis and nontuberculous mycobacterial infections. Coccidioidomycosis was the most likely to cause skin lesions or masses in our patient; however, it was considered less likely because the patient's family had not traveled or been exposed to an endemic area.³  

Benign tumors in the differential include deep hemangioma, which was deemed less likely in our patient because most hemangiomas reach 80% of their maximum size by 5 months of age.⁴ Another possible benign tumor is infantile myofibromatosis, which is rare but is the most common fibrous tumor of infancy.⁵  

Early-onset childhood sarcoidosis also has been shown to produce multiple nontender firm nodules.² This process was considered unlikely in our patient because not only is the disease relatively rare in the pediatric population, but most reported childhood cases have occurred in patients aged 13 to 15 years.⁶ Additionally, no uveitis or arthritis was observed in this case. 

Ultimately, histopathology and bone marrow biopsy were necessary to determine the diagnosis of B-ALL. Although uncommon, cutaneous involvement can be an early sign of ALL in children.⁷ Thus, neoplastic etiologies should be considered in the workup of cutaneous nodules in children, especially when these nodules are hard, rapidly growing, ulcerated, fixed, and/or vascular.⁸ Once the diagnosis is established, initial workup of ALL in children should include complete blood cell count with manual differential, prothrombin time, partial thromboplastin time, electrolytes, uric acid, and renal and liver function tests. Often, baseline viral titers such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, and varicella-zoster virus also are included. Patients are risk stratified to the appropriate level of treatment based on tumor immunophenotype, cytogenetic findings, patient age, white blood cell count at the time of diagnosis, and response to initial therapy. Treatment typically is comprised of a multidrug regimen divided into several phases--induction, consolidation, and maintenance--as well as therapy directed to the central nervous system. Treatment protocols usually take 2 to 3 years to complete.  

Our patient was treated with 1 dose of intrathecal methotrexate before starting the Interfant-06 protocol with a 7-day methylprednisolone prophase. The patient's nodules shrank over time and were no longer present after 14 days of treatment. 

The Diagnosis: B-Cell Acute Lymphoblastic Leukemia 

A 4-mm punch biopsy of one of the scalp lesions showed a diffuse infiltrate of intermediately sized cells with variably mature chromatin and irregular nuclear contours, consistent with a neoplastic process. Numerous mitotic figures were present, indicating a high proliferation rate (Figure 1). At that time there was no evidence of systemic involvement. A repeat biopsy with concurrent bone marrow biopsy was scheduled 10 days after the patient's initial presentation for further classification. Laboratory studies at that time revealed leukocytosis with elevated neutrophils and lymphocytes as well as a high absolute blast count. 

On immunohistochemical staining, the neoplastic cells were positive for CD45, which indicated the neoplasm was hematopoietic, as well as CD10 and the B-cell antigens PAX-5 and CD79a. The cells were negative for CD20, which also is a B-cell marker, but this marker is only expressed in approximately half of pediatric acute lymphoblastic leukemia (ALL) cases with B-cell precursor origin.¹ Markers that typically are expressed in B-cell acute lymphoblastic leukemia (B-ALL)--CD34 and terminal deoxynucleotidyl transferase--were both negative. These results were somewhat contradictory, and the differential remained open to both B-ALL and mature B-cell lymphoma. A bone marrow biopsy showed approximately 65% blasts or leukemic cells (Figure 2). Flow cytometry showed the cells were positive for CD10, CD19, weak CD79a, and variable lambda surface antigen expression. The cells were negative for expression of CD20, CD34, terminal deoxynucleotidyl transferase, myeloid antigens, and CD3. Ultimately, the morphology and immunophenotype were most consistent with a diagnosis of B-ALL. Fluorescence in situ hybridization revealed mixed lineage leukemia, MLL, gene rearrangements.  

Potential oncologic processes include leukemia cutis, lymphoblastic leukemia/lymphoma, Langerhans cell histiocytosis, and rhabdomyosarcoma. Initial laboratory test results were reassuring. Infectious processes in the differential include deep fungal infections such as coccidioidomycosis and nontuberculous mycobacterial infections. Coccidioidomycosis was the most likely to cause skin lesions or masses in our patient; however, it was considered less likely because the patient's family had not traveled or been exposed to an endemic area.³  

Benign tumors in the differential include deep hemangioma, which was deemed less likely in our patient because most hemangiomas reach 80% of their maximum size by 5 months of age.⁴ Another possible benign tumor is infantile myofibromatosis, which is rare but is the most common fibrous tumor of infancy.⁵  

Early-onset childhood sarcoidosis also has been shown to produce multiple nontender firm nodules.² This process was considered unlikely in our patient because not only is the disease relatively rare in the pediatric population, but most reported childhood cases have occurred in patients aged 13 to 15 years.⁶ Additionally, no uveitis or arthritis was observed in this case. 

Ultimately, histopathology and bone marrow biopsy were necessary to determine the diagnosis of B-ALL. Although uncommon, cutaneous involvement can be an early sign of ALL in children.⁷ Thus, neoplastic etiologies should be considered in the workup of cutaneous nodules in children, especially when these nodules are hard, rapidly growing, ulcerated, fixed, and/or vascular.⁸ Once the diagnosis is established, initial workup of ALL in children should include complete blood cell count with manual differential, prothrombin time, partial thromboplastin time, electrolytes, uric acid, and renal and liver function tests. Often, baseline viral titers such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, and varicella-zoster virus also are included. Patients are risk stratified to the appropriate level of treatment based on tumor immunophenotype, cytogenetic findings, patient age, white blood cell count at the time of diagnosis, and response to initial therapy. Treatment typically is comprised of a multidrug regimen divided into several phases--induction, consolidation, and maintenance--as well as therapy directed to the central nervous system. Treatment protocols usually take 2 to 3 years to complete.  

Our patient was treated with 1 dose of intrathecal methotrexate before starting the Interfant-06 protocol with a 7-day methylprednisolone prophase. The patient's nodules shrank over time and were no longer present after 14 days of treatment. 

The Diagnosis: Plasmablastic Lymphoma 

Histopathologic examination revealed a diffuse dense proliferation of large, atypical, and pleomorphic mononuclear cells with prominent nucleoli and many mitotic figures representing plasmacytoid cells in the dermis (Figure). Immunostaining was positive for MUM-1 (marker of late-stage plasma cells and activated T cells) and BCL-2 (antiapoptotic marker). Fluorescent polymerase chain reaction was positive for clonal IgH gene arrangement, and fluorescence in situ hybridization was positive for C-MYC rearrangement in 94% of cells. Epstein-Barr encoding region in situ hybridization also was positive. Rare cells stained positive for T-cell markers. CD20, BCL-6, and CD30 immunostains were negative, suggesting that these cells were not B or T cells, though terminally differentiated B cells also can lack these markers. Bone marrow biopsy showed a similar staining pattern to the skin with 10% atypical plasmacytoid cells. Computed tomography of the left leg showed an enlargement of the semimembranosus muscle with internal areas of high density and heterogeneous enhancement. The patient underwent decompression of the left peroneal nerve. Biopsy showed a staining pattern similar to the right skin nodule and bone marrow, consistent with lymphoma.  

He was diagnosed with stage IV human immunodeficiency virus (HIV)-associated plasmablastic lymphoma (PBL) and received 6 cycles of R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) without vincristine with intrathecal methotrexate, followed by 3 cycles of DHAP (dexamethasone, high dose Ara C, cisplatin) with bortezomib and daratumumab after relapse. Ultimately, he underwent autologous stem cell transplantation and was alive 13 months after diagnosis.  

Plasmablastic lymphoma is a rare subtype of non-Hodgkin lymphoma that most commonly arises in the oral cavity of individuals with HIV.¹ In addition to HIV infection, PBL also is seen in patients with other causes of immunodeficiency such as iatrogenic immunosuppression following solid organ transplantation.¹ The typical disease presentation is an expanding mass in the oral cavity; however, 34% (52/151) of reported cases arose at extraoral primary sites, with a minority of cases confined to cutaneous sites with no systemic involvement.² Cutaneous PBL presentations may include flesh-colored or purple, grouped or solitary nodules; an erythematous infiltrated plaque; or purple-red ulcerated nodules. The lesions usually are asymptomatic and located on the arms and legs.³  

On histologic examination, PBL is characterized by a diffuse monomorphic lymphoid infiltrate that sometimes invades the surrounding soft tissue.^4-6 The neoplastic cells have eccentric round nucleoli. Plasmablastic lymphoma characteristically displays a high proliferation index with many mitotic figures and signs of apoptosis.^4-6 Definitive diagnosis requires immunohistochemical staining. Typical B-cell antigens (CD20) as well as CD45 are negative, while plasma cell markers such as CD38 are positive. Other B- and T-cell markers usually are negative.^5,7 The pathogenesis of PBL is thought to be related to Epstein-Barr virus or human herpesvirus 8 infection. In a series of PBL cases, Epstein-Barr virus and human herpesvirus 8 was positive in 75% (97/129) and 17% (13/75) of tested cases, respectively.¹ 

The prognosis for PBL is poor, with a median overall survival of 15 months and a 3-year survival rate of 25% in HIV-infected individuals.⁸ However, cutaneous PBL without systemic involvement has a considerably better prognosis, with only 1 of 12 cases resulting in death.^2,3,9 Treatment of PBL depends on the extent of the disease. Cutaneous PBL can be treated with surgery and adjuvant radiation.³ Chemotherapy is required for patients with multiple lesions or systemic involvement. Current treatment regimens are similar to those used for other aggressive lymphomas such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).¹ Transplant recipients should have their immunosuppression reduced, and HIV-infected patients should have their highly active antiretroviral therapy regimens optimized. Patients presenting with PBL without HIV should be tested for HIV, as PBL has previously been reported to be the presenting manifestation of HIV infection.¹⁰ 

The differential diagnosis for a rapidly expanding, vascular-appearing, red mass on the legs in an immunosuppressed individual includes abscess, malignancy, Kaposi sarcoma, Sweet syndrome, and tertiary syphilis.  

Acknowledgment
We thank Sameera Husain, MD (New York, New York), for her assistance with histopathologic photographs and interpretation.  

The Diagnosis: Plasmablastic Lymphoma 

Histopathologic examination revealed a diffuse dense proliferation of large, atypical, and pleomorphic mononuclear cells with prominent nucleoli and many mitotic figures representing plasmacytoid cells in the dermis (Figure). Immunostaining was positive for MUM-1 (marker of late-stage plasma cells and activated T cells) and BCL-2 (antiapoptotic marker). Fluorescent polymerase chain reaction was positive for clonal IgH gene arrangement, and fluorescence in situ hybridization was positive for C-MYC rearrangement in 94% of cells. Epstein-Barr encoding region in situ hybridization also was positive. Rare cells stained positive for T-cell markers. CD20, BCL-6, and CD30 immunostains were negative, suggesting that these cells were not B or T cells, though terminally differentiated B cells also can lack these markers. Bone marrow biopsy showed a similar staining pattern to the skin with 10% atypical plasmacytoid cells. Computed tomography of the left leg showed an enlargement of the semimembranosus muscle with internal areas of high density and heterogeneous enhancement. The patient underwent decompression of the left peroneal nerve. Biopsy showed a staining pattern similar to the right skin nodule and bone marrow, consistent with lymphoma.  

He was diagnosed with stage IV human immunodeficiency virus (HIV)-associated plasmablastic lymphoma (PBL) and received 6 cycles of R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) without vincristine with intrathecal methotrexate, followed by 3 cycles of DHAP (dexamethasone, high dose Ara C, cisplatin) with bortezomib and daratumumab after relapse. Ultimately, he underwent autologous stem cell transplantation and was alive 13 months after diagnosis.  

Plasmablastic lymphoma is a rare subtype of non-Hodgkin lymphoma that most commonly arises in the oral cavity of individuals with HIV.¹ In addition to HIV infection, PBL also is seen in patients with other causes of immunodeficiency such as iatrogenic immunosuppression following solid organ transplantation.¹ The typical disease presentation is an expanding mass in the oral cavity; however, 34% (52/151) of reported cases arose at extraoral primary sites, with a minority of cases confined to cutaneous sites with no systemic involvement.² Cutaneous PBL presentations may include flesh-colored or purple, grouped or solitary nodules; an erythematous infiltrated plaque; or purple-red ulcerated nodules. The lesions usually are asymptomatic and located on the arms and legs.³  

On histologic examination, PBL is characterized by a diffuse monomorphic lymphoid infiltrate that sometimes invades the surrounding soft tissue.^4-6 The neoplastic cells have eccentric round nucleoli. Plasmablastic lymphoma characteristically displays a high proliferation index with many mitotic figures and signs of apoptosis.^4-6 Definitive diagnosis requires immunohistochemical staining. Typical B-cell antigens (CD20) as well as CD45 are negative, while plasma cell markers such as CD38 are positive. Other B- and T-cell markers usually are negative.^5,7 The pathogenesis of PBL is thought to be related to Epstein-Barr virus or human herpesvirus 8 infection. In a series of PBL cases, Epstein-Barr virus and human herpesvirus 8 was positive in 75% (97/129) and 17% (13/75) of tested cases, respectively.¹ 

The prognosis for PBL is poor, with a median overall survival of 15 months and a 3-year survival rate of 25% in HIV-infected individuals.⁸ However, cutaneous PBL without systemic involvement has a considerably better prognosis, with only 1 of 12 cases resulting in death.^2,3,9 Treatment of PBL depends on the extent of the disease. Cutaneous PBL can be treated with surgery and adjuvant radiation.³ Chemotherapy is required for patients with multiple lesions or systemic involvement. Current treatment regimens are similar to those used for other aggressive lymphomas such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).¹ Transplant recipients should have their immunosuppression reduced, and HIV-infected patients should have their highly active antiretroviral therapy regimens optimized. Patients presenting with PBL without HIV should be tested for HIV, as PBL has previously been reported to be the presenting manifestation of HIV infection.¹⁰ 

The differential diagnosis for a rapidly expanding, vascular-appearing, red mass on the legs in an immunosuppressed individual includes abscess, malignancy, Kaposi sarcoma, Sweet syndrome, and tertiary syphilis.  

Acknowledgment
We thank Sameera Husain, MD (New York, New York), for her assistance with histopathologic photographs and interpretation.  

The Diagnosis: Plasmablastic Lymphoma 

Histopathologic examination revealed a diffuse dense proliferation of large, atypical, and pleomorphic mononuclear cells with prominent nucleoli and many mitotic figures representing plasmacytoid cells in the dermis (Figure). Immunostaining was positive for MUM-1 (marker of late-stage plasma cells and activated T cells) and BCL-2 (antiapoptotic marker). Fluorescent polymerase chain reaction was positive for clonal IgH gene arrangement, and fluorescence in situ hybridization was positive for C-MYC rearrangement in 94% of cells. Epstein-Barr encoding region in situ hybridization also was positive. Rare cells stained positive for T-cell markers. CD20, BCL-6, and CD30 immunostains were negative, suggesting that these cells were not B or T cells, though terminally differentiated B cells also can lack these markers. Bone marrow biopsy showed a similar staining pattern to the skin with 10% atypical plasmacytoid cells. Computed tomography of the left leg showed an enlargement of the semimembranosus muscle with internal areas of high density and heterogeneous enhancement. The patient underwent decompression of the left peroneal nerve. Biopsy showed a staining pattern similar to the right skin nodule and bone marrow, consistent with lymphoma.  

He was diagnosed with stage IV human immunodeficiency virus (HIV)-associated plasmablastic lymphoma (PBL) and received 6 cycles of R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) without vincristine with intrathecal methotrexate, followed by 3 cycles of DHAP (dexamethasone, high dose Ara C, cisplatin) with bortezomib and daratumumab after relapse. Ultimately, he underwent autologous stem cell transplantation and was alive 13 months after diagnosis.  

Plasmablastic lymphoma is a rare subtype of non-Hodgkin lymphoma that most commonly arises in the oral cavity of individuals with HIV.¹ In addition to HIV infection, PBL also is seen in patients with other causes of immunodeficiency such as iatrogenic immunosuppression following solid organ transplantation.¹ The typical disease presentation is an expanding mass in the oral cavity; however, 34% (52/151) of reported cases arose at extraoral primary sites, with a minority of cases confined to cutaneous sites with no systemic involvement.² Cutaneous PBL presentations may include flesh-colored or purple, grouped or solitary nodules; an erythematous infiltrated plaque; or purple-red ulcerated nodules. The lesions usually are asymptomatic and located on the arms and legs.³  

On histologic examination, PBL is characterized by a diffuse monomorphic lymphoid infiltrate that sometimes invades the surrounding soft tissue.^4-6 The neoplastic cells have eccentric round nucleoli. Plasmablastic lymphoma characteristically displays a high proliferation index with many mitotic figures and signs of apoptosis.^4-6 Definitive diagnosis requires immunohistochemical staining. Typical B-cell antigens (CD20) as well as CD45 are negative, while plasma cell markers such as CD38 are positive. Other B- and T-cell markers usually are negative.^5,7 The pathogenesis of PBL is thought to be related to Epstein-Barr virus or human herpesvirus 8 infection. In a series of PBL cases, Epstein-Barr virus and human herpesvirus 8 was positive in 75% (97/129) and 17% (13/75) of tested cases, respectively.¹ 

The prognosis for PBL is poor, with a median overall survival of 15 months and a 3-year survival rate of 25% in HIV-infected individuals.⁸ However, cutaneous PBL without systemic involvement has a considerably better prognosis, with only 1 of 12 cases resulting in death.^2,3,9 Treatment of PBL depends on the extent of the disease. Cutaneous PBL can be treated with surgery and adjuvant radiation.³ Chemotherapy is required for patients with multiple lesions or systemic involvement. Current treatment regimens are similar to those used for other aggressive lymphomas such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).¹ Transplant recipients should have their immunosuppression reduced, and HIV-infected patients should have their highly active antiretroviral therapy regimens optimized. Patients presenting with PBL without HIV should be tested for HIV, as PBL has previously been reported to be the presenting manifestation of HIV infection.¹⁰ 

The differential diagnosis for a rapidly expanding, vascular-appearing, red mass on the legs in an immunosuppressed individual includes abscess, malignancy, Kaposi sarcoma, Sweet syndrome, and tertiary syphilis.  

Acknowledgment
We thank Sameera Husain, MD (New York, New York), for her assistance with histopathologic photographs and interpretation.  

The Diagnosis: Vestibular Papillomatosis  

Vestibular papillomatosis (VP), the female equivalent of pearly penile papules, is characterized by multiple papules in a linear array on the labia minora and is considered a normal anatomic variant. It typically presents as monomorphous, soft, flesh-colored, filiform papules that are distributed in a symmetric fashion. In women, the papules present as linear arrays on the inner aspects of the labia minora, whereas in men, they present in a circumferential array along the sulcus of the glans penis.¹ Lesions often are asymptomatic but may cause itching, burning, and dyspareunia.² Previously believed to be associated with human papillomavirus infection,³ VP is now considered a noninfectious condition. Biopsy reveals parakeratosis and perinuclear vacuolization in the absence of true koilocytes.^4,5 Dermoscopy and reflectance confocal microscopy have been used to differentiate VP from clinically similar lesions (eg, condyloma acuminatum).^6,7 The prevalence of this condition is not well established; however, one study found VP in 1% of women attending genitourinary medicine clinics.³ 

Condyloma acuminatum, known colloquially as genital warts, is a human papillomavirus infection. Lesions tend to be painless and firm and are distributed asymmetrically with a cauliflowerlike appearance.¹ Condyloma latum, found in secondary syphilis, is characterized by papules that are pale, smooth, flat topped, and moist.⁸ Molluscum contagiosum is an infection caused by a poxvirus presenting with flesh-colored, dome-shaped papules with central umbilication.⁹ The lesions of papulosquamous lichen planus are violaceous polygonal papules that affect the clitoral hood and labia minora and may cause pruritus. The cause of lichen planus is unknown; however, clinically similar lesions may occur in a lichenoid drug eruption due to certain medications. 

Vestibular papillomatosis typically does not require treatment, except in symptomatic cases. To date, limited studies have reported variable treatment success utilizing destructive techniques such as CO2 laser or topical application of 5-fluorouracil or trichloroacetic acid.¹⁰  

The lesions on our patient's left medial labia minora were successfully treated with low-voltage (3.0 V) electrodesiccation. Following local anesthesia with 1% lidocaine, each papule was gently electrodesiccated utilizing a standard hyfrecation electrode tip to a light gray discoloration. Postprocedural care involved only twice-daily cleansing with a gentle soap and application of petrolatum. The patient tolerated the procedure well and was satisfied with the cosmetic and functional results. She subsequently underwent treatment of the lesions on the right labia minora with equivalent treatment success.  
 

The Diagnosis: Vestibular Papillomatosis  

Vestibular papillomatosis (VP), the female equivalent of pearly penile papules, is characterized by multiple papules in a linear array on the labia minora and is considered a normal anatomic variant. It typically presents as monomorphous, soft, flesh-colored, filiform papules that are distributed in a symmetric fashion. In women, the papules present as linear arrays on the inner aspects of the labia minora, whereas in men, they present in a circumferential array along the sulcus of the glans penis.¹ Lesions often are asymptomatic but may cause itching, burning, and dyspareunia.² Previously believed to be associated with human papillomavirus infection,³ VP is now considered a noninfectious condition. Biopsy reveals parakeratosis and perinuclear vacuolization in the absence of true koilocytes.^4,5 Dermoscopy and reflectance confocal microscopy have been used to differentiate VP from clinically similar lesions (eg, condyloma acuminatum).^6,7 The prevalence of this condition is not well established; however, one study found VP in 1% of women attending genitourinary medicine clinics.³ 

Condyloma acuminatum, known colloquially as genital warts, is a human papillomavirus infection. Lesions tend to be painless and firm and are distributed asymmetrically with a cauliflowerlike appearance.¹ Condyloma latum, found in secondary syphilis, is characterized by papules that are pale, smooth, flat topped, and moist.⁸ Molluscum contagiosum is an infection caused by a poxvirus presenting with flesh-colored, dome-shaped papules with central umbilication.⁹ The lesions of papulosquamous lichen planus are violaceous polygonal papules that affect the clitoral hood and labia minora and may cause pruritus. The cause of lichen planus is unknown; however, clinically similar lesions may occur in a lichenoid drug eruption due to certain medications. 

Vestibular papillomatosis typically does not require treatment, except in symptomatic cases. To date, limited studies have reported variable treatment success utilizing destructive techniques such as CO2 laser or topical application of 5-fluorouracil or trichloroacetic acid.¹⁰  

The lesions on our patient's left medial labia minora were successfully treated with low-voltage (3.0 V) electrodesiccation. Following local anesthesia with 1% lidocaine, each papule was gently electrodesiccated utilizing a standard hyfrecation electrode tip to a light gray discoloration. Postprocedural care involved only twice-daily cleansing with a gentle soap and application of petrolatum. The patient tolerated the procedure well and was satisfied with the cosmetic and functional results. She subsequently underwent treatment of the lesions on the right labia minora with equivalent treatment success.  
 

The Diagnosis: Vestibular Papillomatosis  

Vestibular papillomatosis (VP), the female equivalent of pearly penile papules, is characterized by multiple papules in a linear array on the labia minora and is considered a normal anatomic variant. It typically presents as monomorphous, soft, flesh-colored, filiform papules that are distributed in a symmetric fashion. In women, the papules present as linear arrays on the inner aspects of the labia minora, whereas in men, they present in a circumferential array along the sulcus of the glans penis.¹ Lesions often are asymptomatic but may cause itching, burning, and dyspareunia.² Previously believed to be associated with human papillomavirus infection,³ VP is now considered a noninfectious condition. Biopsy reveals parakeratosis and perinuclear vacuolization in the absence of true koilocytes.^4,5 Dermoscopy and reflectance confocal microscopy have been used to differentiate VP from clinically similar lesions (eg, condyloma acuminatum).^6,7 The prevalence of this condition is not well established; however, one study found VP in 1% of women attending genitourinary medicine clinics.³ 

Condyloma acuminatum, known colloquially as genital warts, is a human papillomavirus infection. Lesions tend to be painless and firm and are distributed asymmetrically with a cauliflowerlike appearance.¹ Condyloma latum, found in secondary syphilis, is characterized by papules that are pale, smooth, flat topped, and moist.⁸ Molluscum contagiosum is an infection caused by a poxvirus presenting with flesh-colored, dome-shaped papules with central umbilication.⁹ The lesions of papulosquamous lichen planus are violaceous polygonal papules that affect the clitoral hood and labia minora and may cause pruritus. The cause of lichen planus is unknown; however, clinically similar lesions may occur in a lichenoid drug eruption due to certain medications. 

Vestibular papillomatosis typically does not require treatment, except in symptomatic cases. To date, limited studies have reported variable treatment success utilizing destructive techniques such as CO2 laser or topical application of 5-fluorouracil or trichloroacetic acid.¹⁰  

The lesions on our patient's left medial labia minora were successfully treated with low-voltage (3.0 V) electrodesiccation. Following local anesthesia with 1% lidocaine, each papule was gently electrodesiccated utilizing a standard hyfrecation electrode tip to a light gray discoloration. Postprocedural care involved only twice-daily cleansing with a gentle soap and application of petrolatum. The patient tolerated the procedure well and was satisfied with the cosmetic and functional results. She subsequently underwent treatment of the lesions on the right labia minora with equivalent treatment success.  
 

The Diagnosis: Erosive Adenomatosis of the Nipple 

Biopsy of the lesion revealed proliferative sections of glandular epithelium demonstrating apocrine differentiation, connecting to the epidermis and traversing throughout the entire dermis of the specimen (Figure). There were papillary projections of dilated ducts with a retained layer of myoepithelial cells surrounding the epithelial layers. Cytologic atypia was not appreciated. The patient was diagnosed with erosive adenomatosis of the nipple (EAN), also known as nipple adenoma. The lesion subsequently was treated and cleared with Mohs micrographic surgery (MMS). At 8-month follow-up there was no clinical recurrence of the lesion, and the patient was satisfied with the overall cosmetic appearance and conservation of the areola. The patient was followed clinically with annual breast examinations and mammography to monitor future recurrence. 

Erosive adenomatosis of the nipple is an uncommon benign proliferative process of the lactiferous ducts of the nipple. Recognizing EAN is important because it resembles malignant breast diseases such as Paget disease of the nipple and invasive breast carcinoma. Due to these similarities, early cases of EAN have resulted in unnecessary mastectomies before the benignity of the condition was established.¹ Accurate diagnosis is important to both the patient and the clinician for treatment planning as well as psychosocial consequences associated with the potential removal of this anatomically and cosmetically sensitive area. 

Reviewing the literature on EAN is complicated by the variety of terms used to describe this condition, including but not limited to nipple adenoma, nipple duct adenoma, papillary adenoma of the nipple, and florid papillomatosis of the nipple. In 1955, Jones² described EAN using the term florid papillomatosis of the nipple ducts. In 1962, Handley and Thackray¹ argued that adenoma of the nipple was a more descriptive term because it more closely described the appearance of a sweat gland adenoma. They reasoned that adenoma of the nipple is a separate process from ductal papilloma due to the adenomatous proliferation into the nipple stroma rather than the lumen of the nipple ducts.¹ The term adenoma of the nipple was further supported in 1965 by Taylor and Robertson.³ In 1959, Le Gal et al⁴ used the term erosive adenomatosis of the nipple to describe the erosive nature of nipple adenoma. The term nipple adenoma was published in the 2012 WHO Classification of Tumors of the Breast with 4 common histologic subtypes.^5,6  

Erosive adenomatosis of the nipple is clinically indistinguishable from Paget disease of the nipple, thus biopsy is essential for accurate diagnosis. In contrast to Paget disease, EAN tends to present in younger patients and progresses more slowly, and symptoms may be exacerbated around menstruation.¹ Case reports demonstrate that patients may wait years before seeking medical attention for EAN.^1,3,7,8 Presenting symptoms may include inflammation, crusting, nipple skin erosion, itching, and pain. Serous or sanguineous discharge from the lesions also is commonly reported. Palpation may reveal a small, hard, or elastic nodule within or underlying the nipple. In addition to Paget disease, EAN may resemble squamous cell carcinoma of the nipple, eczema, psoriasis, or a skin infection.⁶ Axillary lymphadenopathy is not present in the absence of a concomitant breast malignancy.⁸ On biopsy, nipple adenoma represents ductal proliferation of glandular structures within the stroma of the nipple that is well circumscribed but without borders. The erosive appearance of the lesion is produced by extensions of the glandular epithelium on the surface of the nipple.^1,6 Specific to EAN is the presence of 2 cell types: an inner columnar epithelium and an outer cuboidal myoepithelium. These 2 cell types are present in normal lactiferous ducts; however, normal ducts are highly organized compared to EAN.⁹  

After confirmation of EAN by nipple biopsy, complete surgical excision has been the gold standard for treatment, followed by reconstructive surgery.⁶ Handley and Thackray¹ advocated for total excision of the nipple and areola with an underlying wedge of breast tissue to facilitate wound closure. More recently, successful alternative forms of treatment have been utilized to minimize disfiguring surgery. Alternative treatments include MMS,⁸ cryotherapy,¹⁰ and nipple splitting enucleation.⁶ Treatment with MMS has resulted in nipple sparing with the least amount of surface area sacrificed (1.1 cm2).⁹ Our case and prior case reports demonstrate that the tissue sparing potential of MMS is appropriate for the treatment of EAN, though traditionally it has been reserved for more malignant tumors. Preserving this sensitive area is both cosmetically and psychologically advantageous for the patient and thus should be considered when reviewing treatment options for EAN. 

The Diagnosis: Erosive Adenomatosis of the Nipple 

Biopsy of the lesion revealed proliferative sections of glandular epithelium demonstrating apocrine differentiation, connecting to the epidermis and traversing throughout the entire dermis of the specimen (Figure). There were papillary projections of dilated ducts with a retained layer of myoepithelial cells surrounding the epithelial layers. Cytologic atypia was not appreciated. The patient was diagnosed with erosive adenomatosis of the nipple (EAN), also known as nipple adenoma. The lesion subsequently was treated and cleared with Mohs micrographic surgery (MMS). At 8-month follow-up there was no clinical recurrence of the lesion, and the patient was satisfied with the overall cosmetic appearance and conservation of the areola. The patient was followed clinically with annual breast examinations and mammography to monitor future recurrence. 

Erosive adenomatosis of the nipple is an uncommon benign proliferative process of the lactiferous ducts of the nipple. Recognizing EAN is important because it resembles malignant breast diseases such as Paget disease of the nipple and invasive breast carcinoma. Due to these similarities, early cases of EAN have resulted in unnecessary mastectomies before the benignity of the condition was established.¹ Accurate diagnosis is important to both the patient and the clinician for treatment planning as well as psychosocial consequences associated with the potential removal of this anatomically and cosmetically sensitive area. 

Reviewing the literature on EAN is complicated by the variety of terms used to describe this condition, including but not limited to nipple adenoma, nipple duct adenoma, papillary adenoma of the nipple, and florid papillomatosis of the nipple. In 1955, Jones² described EAN using the term florid papillomatosis of the nipple ducts. In 1962, Handley and Thackray¹ argued that adenoma of the nipple was a more descriptive term because it more closely described the appearance of a sweat gland adenoma. They reasoned that adenoma of the nipple is a separate process from ductal papilloma due to the adenomatous proliferation into the nipple stroma rather than the lumen of the nipple ducts.¹ The term adenoma of the nipple was further supported in 1965 by Taylor and Robertson.³ In 1959, Le Gal et al⁴ used the term erosive adenomatosis of the nipple to describe the erosive nature of nipple adenoma. The term nipple adenoma was published in the 2012 WHO Classification of Tumors of the Breast with 4 common histologic subtypes.^5,6  

Erosive adenomatosis of the nipple is clinically indistinguishable from Paget disease of the nipple, thus biopsy is essential for accurate diagnosis. In contrast to Paget disease, EAN tends to present in younger patients and progresses more slowly, and symptoms may be exacerbated around menstruation.¹ Case reports demonstrate that patients may wait years before seeking medical attention for EAN.^1,3,7,8 Presenting symptoms may include inflammation, crusting, nipple skin erosion, itching, and pain. Serous or sanguineous discharge from the lesions also is commonly reported. Palpation may reveal a small, hard, or elastic nodule within or underlying the nipple. In addition to Paget disease, EAN may resemble squamous cell carcinoma of the nipple, eczema, psoriasis, or a skin infection.⁶ Axillary lymphadenopathy is not present in the absence of a concomitant breast malignancy.⁸ On biopsy, nipple adenoma represents ductal proliferation of glandular structures within the stroma of the nipple that is well circumscribed but without borders. The erosive appearance of the lesion is produced by extensions of the glandular epithelium on the surface of the nipple.^1,6 Specific to EAN is the presence of 2 cell types: an inner columnar epithelium and an outer cuboidal myoepithelium. These 2 cell types are present in normal lactiferous ducts; however, normal ducts are highly organized compared to EAN.⁹  

After confirmation of EAN by nipple biopsy, complete surgical excision has been the gold standard for treatment, followed by reconstructive surgery.⁶ Handley and Thackray¹ advocated for total excision of the nipple and areola with an underlying wedge of breast tissue to facilitate wound closure. More recently, successful alternative forms of treatment have been utilized to minimize disfiguring surgery. Alternative treatments include MMS,⁸ cryotherapy,¹⁰ and nipple splitting enucleation.⁶ Treatment with MMS has resulted in nipple sparing with the least amount of surface area sacrificed (1.1 cm2).⁹ Our case and prior case reports demonstrate that the tissue sparing potential of MMS is appropriate for the treatment of EAN, though traditionally it has been reserved for more malignant tumors. Preserving this sensitive area is both cosmetically and psychologically advantageous for the patient and thus should be considered when reviewing treatment options for EAN. 

The Diagnosis: Erosive Adenomatosis of the Nipple 

Biopsy of the lesion revealed proliferative sections of glandular epithelium demonstrating apocrine differentiation, connecting to the epidermis and traversing throughout the entire dermis of the specimen (Figure). There were papillary projections of dilated ducts with a retained layer of myoepithelial cells surrounding the epithelial layers. Cytologic atypia was not appreciated. The patient was diagnosed with erosive adenomatosis of the nipple (EAN), also known as nipple adenoma. The lesion subsequently was treated and cleared with Mohs micrographic surgery (MMS). At 8-month follow-up there was no clinical recurrence of the lesion, and the patient was satisfied with the overall cosmetic appearance and conservation of the areola. The patient was followed clinically with annual breast examinations and mammography to monitor future recurrence. 

Erosive adenomatosis of the nipple is an uncommon benign proliferative process of the lactiferous ducts of the nipple. Recognizing EAN is important because it resembles malignant breast diseases such as Paget disease of the nipple and invasive breast carcinoma. Due to these similarities, early cases of EAN have resulted in unnecessary mastectomies before the benignity of the condition was established.¹ Accurate diagnosis is important to both the patient and the clinician for treatment planning as well as psychosocial consequences associated with the potential removal of this anatomically and cosmetically sensitive area. 

Reviewing the literature on EAN is complicated by the variety of terms used to describe this condition, including but not limited to nipple adenoma, nipple duct adenoma, papillary adenoma of the nipple, and florid papillomatosis of the nipple. In 1955, Jones² described EAN using the term florid papillomatosis of the nipple ducts. In 1962, Handley and Thackray¹ argued that adenoma of the nipple was a more descriptive term because it more closely described the appearance of a sweat gland adenoma. They reasoned that adenoma of the nipple is a separate process from ductal papilloma due to the adenomatous proliferation into the nipple stroma rather than the lumen of the nipple ducts.¹ The term adenoma of the nipple was further supported in 1965 by Taylor and Robertson.³ In 1959, Le Gal et al⁴ used the term erosive adenomatosis of the nipple to describe the erosive nature of nipple adenoma. The term nipple adenoma was published in the 2012 WHO Classification of Tumors of the Breast with 4 common histologic subtypes.^5,6  

Erosive adenomatosis of the nipple is clinically indistinguishable from Paget disease of the nipple, thus biopsy is essential for accurate diagnosis. In contrast to Paget disease, EAN tends to present in younger patients and progresses more slowly, and symptoms may be exacerbated around menstruation.¹ Case reports demonstrate that patients may wait years before seeking medical attention for EAN.^1,3,7,8 Presenting symptoms may include inflammation, crusting, nipple skin erosion, itching, and pain. Serous or sanguineous discharge from the lesions also is commonly reported. Palpation may reveal a small, hard, or elastic nodule within or underlying the nipple. In addition to Paget disease, EAN may resemble squamous cell carcinoma of the nipple, eczema, psoriasis, or a skin infection.⁶ Axillary lymphadenopathy is not present in the absence of a concomitant breast malignancy.⁸ On biopsy, nipple adenoma represents ductal proliferation of glandular structures within the stroma of the nipple that is well circumscribed but without borders. The erosive appearance of the lesion is produced by extensions of the glandular epithelium on the surface of the nipple.^1,6 Specific to EAN is the presence of 2 cell types: an inner columnar epithelium and an outer cuboidal myoepithelium. These 2 cell types are present in normal lactiferous ducts; however, normal ducts are highly organized compared to EAN.⁹  

After confirmation of EAN by nipple biopsy, complete surgical excision has been the gold standard for treatment, followed by reconstructive surgery.⁶ Handley and Thackray¹ advocated for total excision of the nipple and areola with an underlying wedge of breast tissue to facilitate wound closure. More recently, successful alternative forms of treatment have been utilized to minimize disfiguring surgery. Alternative treatments include MMS,⁸ cryotherapy,¹⁰ and nipple splitting enucleation.⁶ Treatment with MMS has resulted in nipple sparing with the least amount of surface area sacrificed (1.1 cm2).⁹ Our case and prior case reports demonstrate that the tissue sparing potential of MMS is appropriate for the treatment of EAN, though traditionally it has been reserved for more malignant tumors. Preserving this sensitive area is both cosmetically and psychologically advantageous for the patient and thus should be considered when reviewing treatment options for EAN.