Dermatopathology

The Diagnosis: Nodular Hidradenoma

Nodular hidradenomas (NHs) are rare benign cutaneous adnexal neoplasms first described in 1949 as clear cell papillary carcinomas.¹ Since then, various terms have been used to describe this entity, such as eccrine acrospiroma, solid-cystic hidradenoma, and clear cell hidradenoma.² Review of the literature revealed a female predominance (2:1 ratio) and a mean age at presentation of 37.2 years.^3,4 Nodular hidradenoma presents as an asymptomatic, solitary, mobile, firm nodule with intact overlying skin. Rarely, multiple nodules may occur.³ Some tumors display ulceration and serous fluid leakage.⁵ They occur most commonly on the scalp, face, and upper extremities with an average size of 2 cm.³ Rapid growth of the tumor may signal a malignant change.⁶

Histopathology reveals a lobulated, circumscribed, symmetrical tumor with dermal nests of epithelial cells that are polygonal with eosinophilic cytoplasm forming ductlike spaces (Figure). However, clear cell changes and squamous differentiation may be prominent features. Cystic spaces may result from tumor cell degeneration. Most tumors are encased by collagenous fibrous tissue and rarely have epidermal attachments.³

Anastomosing aggregates of squamous cells forming ductlike spaces were viewed on low-power magnification (A)(H&E, original magnification ×10). On higher power there were ductlike spaces and eosinophilic hyalinized stroma entrapped by the bland-appearing squamous proliferation (B)(H&E, original magnification ×20).

Nodular hidradenoma traditionally has been considered to be of eccrine origin, but more recent literature indicates that the majority of NHs are of apocrine origin. Histologically, apocrine tumors display eosinophilic secretion, mucinous epithelium, squamous or sebaceous differentiation, and decapitation secretion, whereas eccrine tumors are identified by their lack of specific features.³

Nodular hidradenoma may recur after excision. Malignant transformation is rare. In one review, 6.7% (6/89) of NHs were malignant, characterized by abnormal mitoses, nuclear atypia, and necrosis.⁴ Malignant NH or nodular hidradenocarcinoma behaves aggressively with up to an 86% local recurrence and 60% rate of metastasis within 2 years.⁶ Survival time is inversely proportional to the size of the tumor and is generally poor, with a 5-year disease-free survival of less than 30%.^6,7

Treatment of NH is achieved through primary excision or Mohs micrographic surgery; however, treatment of nodular hidradenocarcinoma is controversial and typically begins with wide local excision but may involve lymph node dissection if necessary. Use of adjuvant chemotherapy and radiation therapy for metastases warrants more clinical studies, as it is a rare occurrence.⁶ Our patient planned to undergo a total excision of the benign nodule once she healed from the biopsy; however, she was lost to follow-up, as she moved out of state.

The Diagnosis: Nodular Hidradenoma

Nodular hidradenomas (NHs) are rare benign cutaneous adnexal neoplasms first described in 1949 as clear cell papillary carcinomas.¹ Since then, various terms have been used to describe this entity, such as eccrine acrospiroma, solid-cystic hidradenoma, and clear cell hidradenoma.² Review of the literature revealed a female predominance (2:1 ratio) and a mean age at presentation of 37.2 years.^3,4 Nodular hidradenoma presents as an asymptomatic, solitary, mobile, firm nodule with intact overlying skin. Rarely, multiple nodules may occur.³ Some tumors display ulceration and serous fluid leakage.⁵ They occur most commonly on the scalp, face, and upper extremities with an average size of 2 cm.³ Rapid growth of the tumor may signal a malignant change.⁶

Histopathology reveals a lobulated, circumscribed, symmetrical tumor with dermal nests of epithelial cells that are polygonal with eosinophilic cytoplasm forming ductlike spaces (Figure). However, clear cell changes and squamous differentiation may be prominent features. Cystic spaces may result from tumor cell degeneration. Most tumors are encased by collagenous fibrous tissue and rarely have epidermal attachments.³

Anastomosing aggregates of squamous cells forming ductlike spaces were viewed on low-power magnification (A)(H&E, original magnification ×10). On higher power there were ductlike spaces and eosinophilic hyalinized stroma entrapped by the bland-appearing squamous proliferation (B)(H&E, original magnification ×20).

Nodular hidradenoma traditionally has been considered to be of eccrine origin, but more recent literature indicates that the majority of NHs are of apocrine origin. Histologically, apocrine tumors display eosinophilic secretion, mucinous epithelium, squamous or sebaceous differentiation, and decapitation secretion, whereas eccrine tumors are identified by their lack of specific features.³

Nodular hidradenoma may recur after excision. Malignant transformation is rare. In one review, 6.7% (6/89) of NHs were malignant, characterized by abnormal mitoses, nuclear atypia, and necrosis.⁴ Malignant NH or nodular hidradenocarcinoma behaves aggressively with up to an 86% local recurrence and 60% rate of metastasis within 2 years.⁶ Survival time is inversely proportional to the size of the tumor and is generally poor, with a 5-year disease-free survival of less than 30%.^6,7

Treatment of NH is achieved through primary excision or Mohs micrographic surgery; however, treatment of nodular hidradenocarcinoma is controversial and typically begins with wide local excision but may involve lymph node dissection if necessary. Use of adjuvant chemotherapy and radiation therapy for metastases warrants more clinical studies, as it is a rare occurrence.⁶ Our patient planned to undergo a total excision of the benign nodule once she healed from the biopsy; however, she was lost to follow-up, as she moved out of state.

The Diagnosis: Nodular Hidradenoma

Nodular hidradenomas (NHs) are rare benign cutaneous adnexal neoplasms first described in 1949 as clear cell papillary carcinomas.¹ Since then, various terms have been used to describe this entity, such as eccrine acrospiroma, solid-cystic hidradenoma, and clear cell hidradenoma.² Review of the literature revealed a female predominance (2:1 ratio) and a mean age at presentation of 37.2 years.^3,4 Nodular hidradenoma presents as an asymptomatic, solitary, mobile, firm nodule with intact overlying skin. Rarely, multiple nodules may occur.³ Some tumors display ulceration and serous fluid leakage.⁵ They occur most commonly on the scalp, face, and upper extremities with an average size of 2 cm.³ Rapid growth of the tumor may signal a malignant change.⁶

Histopathology reveals a lobulated, circumscribed, symmetrical tumor with dermal nests of epithelial cells that are polygonal with eosinophilic cytoplasm forming ductlike spaces (Figure). However, clear cell changes and squamous differentiation may be prominent features. Cystic spaces may result from tumor cell degeneration. Most tumors are encased by collagenous fibrous tissue and rarely have epidermal attachments.³

Anastomosing aggregates of squamous cells forming ductlike spaces were viewed on low-power magnification (A)(H&E, original magnification ×10). On higher power there were ductlike spaces and eosinophilic hyalinized stroma entrapped by the bland-appearing squamous proliferation (B)(H&E, original magnification ×20).

Nodular hidradenoma traditionally has been considered to be of eccrine origin, but more recent literature indicates that the majority of NHs are of apocrine origin. Histologically, apocrine tumors display eosinophilic secretion, mucinous epithelium, squamous or sebaceous differentiation, and decapitation secretion, whereas eccrine tumors are identified by their lack of specific features.³

Nodular hidradenoma may recur after excision. Malignant transformation is rare. In one review, 6.7% (6/89) of NHs were malignant, characterized by abnormal mitoses, nuclear atypia, and necrosis.⁴ Malignant NH or nodular hidradenocarcinoma behaves aggressively with up to an 86% local recurrence and 60% rate of metastasis within 2 years.⁶ Survival time is inversely proportional to the size of the tumor and is generally poor, with a 5-year disease-free survival of less than 30%.^6,7

Treatment of NH is achieved through primary excision or Mohs micrographic surgery; however, treatment of nodular hidradenocarcinoma is controversial and typically begins with wide local excision but may involve lymph node dissection if necessary. Use of adjuvant chemotherapy and radiation therapy for metastases warrants more clinical studies, as it is a rare occurrence.⁶ Our patient planned to undergo a total excision of the benign nodule once she healed from the biopsy; however, she was lost to follow-up, as she moved out of state.

Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8) infection that is conventionally divided into 4 clinical variants: classic, African, transplant associated, and AIDS related. In the United States, classic KS predominantly is observed in elderly white men of Ashkenazi Jewish or Mediterranean descent.¹

The clinical and histological changes seen in KS can be confused with those from chronic venous insufficiency. Both conditions tend to present with purple-colored patches, plaques, or nodules on the lower extremities. Histologically, both KS and chronic venous insufficiency are characterized by blood vessel and endothelial cell proliferation in the papillary dermis, red blood cell extravasation, and hemosiderin deposition.² Nevertheless, KS can be diagnosed based on the presence of neoplastic spindle-shaped cells and positive immunostaining for HHV-8 antigen.³

We describe the cases of 2 elderly Hispanic patients in the United States with no history of human immunodeficiency virus (HIV), immunosuppression, or travel to the Mediterranean region who presented with erythematous to violaceous papules, plaques, and nodules on the distal lower extremities in the setting of chronic venous insufficiency. We review the relationship between KS and chronic venous insufficiency and suggest that these presentations may represent a distinct clinical variant of KS.

Case Reports

Patient 1

An 83-year-old Hispanic woman with a history of hypertension, atrial fibrillation, and chronic venous insufficiency presented with a chronic painful violaceous eruption on the lower legs of 3 years’ duration. The patient reported that the erythematous patches, which she described as bruiselike, originally developed 3 years prior after starting warfarin therapy for atrial fibrillation. At that time, a biopsy indicated findings of pigmented purpuric dermatosis and negative immunostaining for HHV-8. Her condition had worsened over the last 6 months with the development of tender eroded plaques on the dorsal aspects of the feet (Figure 1) and purple-brown patches and plaques on the legs. Prior treatment with topical corticosteroids and a short course of prednisone was unsuccessful. Of note, the patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent.

Punch biopsies from the left dorsal foot and left lower leg revealed dermal fibrosis, a proliferation of small blood vessels with plump endothelial cells, and foci of spindled endothelial cells with narrow slitlike spaces containing erythrocytes (Figure 2). There also were extravasated erythrocytes and a sparse inflammatory cell infiltrate comprised of lymphocytes, eosinophils, neutrophils, and plasma cells. Perls Prussian blue stain highlighted numerous siderophages scattered in the dermis. Based on these findings, immunostaining for HHV-8 was performed and highlighted reactivity of the spindled cells (Figure 3). The patient was diagnosed with KS in the setting of chronic venous insufficiency.

Figure 2. Dermal fibrosis, proliferation of small blood vessels, and spindled endothelial cells with narrow slitlike spaces were observed (H&E, original magnification ×100).   Figure 3. Spindled cells reactive to human herpesvirus 8 immunostaining (original magnification ×100).

Patient 2

A 67-year-old Hispanic man with a history of diabetes mellitus presented with 10 asymptomatic purple papules and hyperkeratotic and hyperpigmented plaques on the distal aspect of the legs of 1 year’s duration in the setting of chronic venous insufficiency (Figure 4). The patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent. An excisional biopsy from the left fourth toe revealed a cellular dermal vascular proliferation associated with numerous small slitlike vessels and scattered dilated blood vessels with prominent hemorrhage and surrounding dermal fibrosis (Figure 5). The lesion was markedly cellular with nuclear atypia. Many cells showed enlarged oval- to spindle-shaped hyperchromatic nuclei, some with prominent nucleoli and scant amounts of eosinophilic cytoplasm. Although the differential diagnosis included an unusual cellular pyogenic granuloma with atypia in the setting of chronic venous insufficiency, the degree of cellularity and presence of spindled cells associated with slitlike vessels were more consistent with a pyogenic granulomalike variant of KS. This variant is rare but has previously been reported.⁴ Many of the tumor nucleoli stained strongly for HHV-8, which is a diagnostic finding of KS (Figure 6). The patient subsequently was diagnosed with KS.

Comment

These 2 cases represent unusual clinical presentations of KS in Hispanic patients with no known risk factors for KS. In patient 1, an initial skin biopsy prompted HHV-8 testing due to suspicion for KS. At that time, HHV-8 was negative, perhaps because of technical deficiencies in the staining protocol; alternatively, the patient may have subsequently developed KS. Both patients had known chronic venous insufficiency. However, biopsies revealed spindle-shaped cells forming clefts and positivity for HHV-8. We propose that these cases may represent an additional clinical variant of KS, chronic venous insufficiency–associated KS.

If similar presentations of KS are identified, studies will need to be done to uncover the specific risk factors involved. Human herpesvirus 8 is not sufficient for the development of KS on its own, as oncogenesis of KS requires immunodeficiency or an additional environmental factor such as diabetes mellitus.5 Through impaired microvascular circulation and the release of hypoxia-inducible factor 1a, diabetes can promote KS-herpesvirus replication. Therefore, the risk for KS is increased in individuals with diabetes regardless of a negative history of immunodeficiency, which may have been the case in patient 2.

Our cases suggest that chronic venous insufficiency may be another factor that predisposes immunocompetent individuals to KS. Chronic venous insufficiency can cause hypoxia, promoting the release of cytokines and angiogenic factors responsible for the formation of vascular tumors such as KS.⁶ Once present, KS can worsen preexisting stasis dermatitis by compressing the external lymphatics and exacerbating lymphedema.⁷ Stasis dermatitis and KS may be part of a self-perpetuating cycle that involves obstruction due to secondary lymphadenopathy, the development of lymphedema, and the release of cytokines and growth factors that lead to further vascular proliferation.⁸

Figure 5. A cellular dermal vascular proliferation associated with slitlike vessels, dermal fibrosis, and marked cellularity with nuclear atypia (H&E, original magnification ×200).

Figure 6. Spindled cells reactive to human herpesvirus 8 immunostain (original magnification ×400).

In summary, we present 2 cases of non–HIV-related KS that may represent an additional clinical variant of KS that mimics and/or arises in chronic venous insufficiency and appears as papules and plaques in elderly patients who are Hispanic, immunocompetent, and HIV negative. We suggest including KS in the differential diagnosis for chronic venous insufficiency, especially in cases with an unusual clinical appearance or course. In these cases, skin biopsy with HHV-8 testing may be warranted.

Acknowledgment

The authors would like to acknowledge William Putnam, BFA, New York, New York, for his assistance with the figures.

Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8) infection that is conventionally divided into 4 clinical variants: classic, African, transplant associated, and AIDS related. In the United States, classic KS predominantly is observed in elderly white men of Ashkenazi Jewish or Mediterranean descent.¹

The clinical and histological changes seen in KS can be confused with those from chronic venous insufficiency. Both conditions tend to present with purple-colored patches, plaques, or nodules on the lower extremities. Histologically, both KS and chronic venous insufficiency are characterized by blood vessel and endothelial cell proliferation in the papillary dermis, red blood cell extravasation, and hemosiderin deposition.² Nevertheless, KS can be diagnosed based on the presence of neoplastic spindle-shaped cells and positive immunostaining for HHV-8 antigen.³

We describe the cases of 2 elderly Hispanic patients in the United States with no history of human immunodeficiency virus (HIV), immunosuppression, or travel to the Mediterranean region who presented with erythematous to violaceous papules, plaques, and nodules on the distal lower extremities in the setting of chronic venous insufficiency. We review the relationship between KS and chronic venous insufficiency and suggest that these presentations may represent a distinct clinical variant of KS.

Case Reports

Patient 1

An 83-year-old Hispanic woman with a history of hypertension, atrial fibrillation, and chronic venous insufficiency presented with a chronic painful violaceous eruption on the lower legs of 3 years’ duration. The patient reported that the erythematous patches, which she described as bruiselike, originally developed 3 years prior after starting warfarin therapy for atrial fibrillation. At that time, a biopsy indicated findings of pigmented purpuric dermatosis and negative immunostaining for HHV-8. Her condition had worsened over the last 6 months with the development of tender eroded plaques on the dorsal aspects of the feet (Figure 1) and purple-brown patches and plaques on the legs. Prior treatment with topical corticosteroids and a short course of prednisone was unsuccessful. Of note, the patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent.

Punch biopsies from the left dorsal foot and left lower leg revealed dermal fibrosis, a proliferation of small blood vessels with plump endothelial cells, and foci of spindled endothelial cells with narrow slitlike spaces containing erythrocytes (Figure 2). There also were extravasated erythrocytes and a sparse inflammatory cell infiltrate comprised of lymphocytes, eosinophils, neutrophils, and plasma cells. Perls Prussian blue stain highlighted numerous siderophages scattered in the dermis. Based on these findings, immunostaining for HHV-8 was performed and highlighted reactivity of the spindled cells (Figure 3). The patient was diagnosed with KS in the setting of chronic venous insufficiency.

Figure 2. Dermal fibrosis, proliferation of small blood vessels, and spindled endothelial cells with narrow slitlike spaces were observed (H&E, original magnification ×100).   Figure 3. Spindled cells reactive to human herpesvirus 8 immunostaining (original magnification ×100).

Patient 2

A 67-year-old Hispanic man with a history of diabetes mellitus presented with 10 asymptomatic purple papules and hyperkeratotic and hyperpigmented plaques on the distal aspect of the legs of 1 year’s duration in the setting of chronic venous insufficiency (Figure 4). The patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent. An excisional biopsy from the left fourth toe revealed a cellular dermal vascular proliferation associated with numerous small slitlike vessels and scattered dilated blood vessels with prominent hemorrhage and surrounding dermal fibrosis (Figure 5). The lesion was markedly cellular with nuclear atypia. Many cells showed enlarged oval- to spindle-shaped hyperchromatic nuclei, some with prominent nucleoli and scant amounts of eosinophilic cytoplasm. Although the differential diagnosis included an unusual cellular pyogenic granuloma with atypia in the setting of chronic venous insufficiency, the degree of cellularity and presence of spindled cells associated with slitlike vessels were more consistent with a pyogenic granulomalike variant of KS. This variant is rare but has previously been reported.⁴ Many of the tumor nucleoli stained strongly for HHV-8, which is a diagnostic finding of KS (Figure 6). The patient subsequently was diagnosed with KS.

Comment

These 2 cases represent unusual clinical presentations of KS in Hispanic patients with no known risk factors for KS. In patient 1, an initial skin biopsy prompted HHV-8 testing due to suspicion for KS. At that time, HHV-8 was negative, perhaps because of technical deficiencies in the staining protocol; alternatively, the patient may have subsequently developed KS. Both patients had known chronic venous insufficiency. However, biopsies revealed spindle-shaped cells forming clefts and positivity for HHV-8. We propose that these cases may represent an additional clinical variant of KS, chronic venous insufficiency–associated KS.

If similar presentations of KS are identified, studies will need to be done to uncover the specific risk factors involved. Human herpesvirus 8 is not sufficient for the development of KS on its own, as oncogenesis of KS requires immunodeficiency or an additional environmental factor such as diabetes mellitus.5 Through impaired microvascular circulation and the release of hypoxia-inducible factor 1a, diabetes can promote KS-herpesvirus replication. Therefore, the risk for KS is increased in individuals with diabetes regardless of a negative history of immunodeficiency, which may have been the case in patient 2.

Our cases suggest that chronic venous insufficiency may be another factor that predisposes immunocompetent individuals to KS. Chronic venous insufficiency can cause hypoxia, promoting the release of cytokines and angiogenic factors responsible for the formation of vascular tumors such as KS.⁶ Once present, KS can worsen preexisting stasis dermatitis by compressing the external lymphatics and exacerbating lymphedema.⁷ Stasis dermatitis and KS may be part of a self-perpetuating cycle that involves obstruction due to secondary lymphadenopathy, the development of lymphedema, and the release of cytokines and growth factors that lead to further vascular proliferation.⁸

Figure 5. A cellular dermal vascular proliferation associated with slitlike vessels, dermal fibrosis, and marked cellularity with nuclear atypia (H&E, original magnification ×200).

Figure 6. Spindled cells reactive to human herpesvirus 8 immunostain (original magnification ×400).

In summary, we present 2 cases of non–HIV-related KS that may represent an additional clinical variant of KS that mimics and/or arises in chronic venous insufficiency and appears as papules and plaques in elderly patients who are Hispanic, immunocompetent, and HIV negative. We suggest including KS in the differential diagnosis for chronic venous insufficiency, especially in cases with an unusual clinical appearance or course. In these cases, skin biopsy with HHV-8 testing may be warranted.

Acknowledgment

The authors would like to acknowledge William Putnam, BFA, New York, New York, for his assistance with the figures.

Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8) infection that is conventionally divided into 4 clinical variants: classic, African, transplant associated, and AIDS related. In the United States, classic KS predominantly is observed in elderly white men of Ashkenazi Jewish or Mediterranean descent.¹

The clinical and histological changes seen in KS can be confused with those from chronic venous insufficiency. Both conditions tend to present with purple-colored patches, plaques, or nodules on the lower extremities. Histologically, both KS and chronic venous insufficiency are characterized by blood vessel and endothelial cell proliferation in the papillary dermis, red blood cell extravasation, and hemosiderin deposition.² Nevertheless, KS can be diagnosed based on the presence of neoplastic spindle-shaped cells and positive immunostaining for HHV-8 antigen.³

We describe the cases of 2 elderly Hispanic patients in the United States with no history of human immunodeficiency virus (HIV), immunosuppression, or travel to the Mediterranean region who presented with erythematous to violaceous papules, plaques, and nodules on the distal lower extremities in the setting of chronic venous insufficiency. We review the relationship between KS and chronic venous insufficiency and suggest that these presentations may represent a distinct clinical variant of KS.

Case Reports

Patient 1

An 83-year-old Hispanic woman with a history of hypertension, atrial fibrillation, and chronic venous insufficiency presented with a chronic painful violaceous eruption on the lower legs of 3 years’ duration. The patient reported that the erythematous patches, which she described as bruiselike, originally developed 3 years prior after starting warfarin therapy for atrial fibrillation. At that time, a biopsy indicated findings of pigmented purpuric dermatosis and negative immunostaining for HHV-8. Her condition had worsened over the last 6 months with the development of tender eroded plaques on the dorsal aspects of the feet (Figure 1) and purple-brown patches and plaques on the legs. Prior treatment with topical corticosteroids and a short course of prednisone was unsuccessful. Of note, the patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent.

Punch biopsies from the left dorsal foot and left lower leg revealed dermal fibrosis, a proliferation of small blood vessels with plump endothelial cells, and foci of spindled endothelial cells with narrow slitlike spaces containing erythrocytes (Figure 2). There also were extravasated erythrocytes and a sparse inflammatory cell infiltrate comprised of lymphocytes, eosinophils, neutrophils, and plasma cells. Perls Prussian blue stain highlighted numerous siderophages scattered in the dermis. Based on these findings, immunostaining for HHV-8 was performed and highlighted reactivity of the spindled cells (Figure 3). The patient was diagnosed with KS in the setting of chronic venous insufficiency.

Figure 2. Dermal fibrosis, proliferation of small blood vessels, and spindled endothelial cells with narrow slitlike spaces were observed (H&E, original magnification ×100).   Figure 3. Spindled cells reactive to human herpesvirus 8 immunostaining (original magnification ×100).

Patient 2

A 67-year-old Hispanic man with a history of diabetes mellitus presented with 10 asymptomatic purple papules and hyperkeratotic and hyperpigmented plaques on the distal aspect of the legs of 1 year’s duration in the setting of chronic venous insufficiency (Figure 4). The patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent. An excisional biopsy from the left fourth toe revealed a cellular dermal vascular proliferation associated with numerous small slitlike vessels and scattered dilated blood vessels with prominent hemorrhage and surrounding dermal fibrosis (Figure 5). The lesion was markedly cellular with nuclear atypia. Many cells showed enlarged oval- to spindle-shaped hyperchromatic nuclei, some with prominent nucleoli and scant amounts of eosinophilic cytoplasm. Although the differential diagnosis included an unusual cellular pyogenic granuloma with atypia in the setting of chronic venous insufficiency, the degree of cellularity and presence of spindled cells associated with slitlike vessels were more consistent with a pyogenic granulomalike variant of KS. This variant is rare but has previously been reported.⁴ Many of the tumor nucleoli stained strongly for HHV-8, which is a diagnostic finding of KS (Figure 6). The patient subsequently was diagnosed with KS.

Comment

These 2 cases represent unusual clinical presentations of KS in Hispanic patients with no known risk factors for KS. In patient 1, an initial skin biopsy prompted HHV-8 testing due to suspicion for KS. At that time, HHV-8 was negative, perhaps because of technical deficiencies in the staining protocol; alternatively, the patient may have subsequently developed KS. Both patients had known chronic venous insufficiency. However, biopsies revealed spindle-shaped cells forming clefts and positivity for HHV-8. We propose that these cases may represent an additional clinical variant of KS, chronic venous insufficiency–associated KS.

If similar presentations of KS are identified, studies will need to be done to uncover the specific risk factors involved. Human herpesvirus 8 is not sufficient for the development of KS on its own, as oncogenesis of KS requires immunodeficiency or an additional environmental factor such as diabetes mellitus.5 Through impaired microvascular circulation and the release of hypoxia-inducible factor 1a, diabetes can promote KS-herpesvirus replication. Therefore, the risk for KS is increased in individuals with diabetes regardless of a negative history of immunodeficiency, which may have been the case in patient 2.

Our cases suggest that chronic venous insufficiency may be another factor that predisposes immunocompetent individuals to KS. Chronic venous insufficiency can cause hypoxia, promoting the release of cytokines and angiogenic factors responsible for the formation of vascular tumors such as KS.⁶ Once present, KS can worsen preexisting stasis dermatitis by compressing the external lymphatics and exacerbating lymphedema.⁷ Stasis dermatitis and KS may be part of a self-perpetuating cycle that involves obstruction due to secondary lymphadenopathy, the development of lymphedema, and the release of cytokines and growth factors that lead to further vascular proliferation.⁸

Figure 5. A cellular dermal vascular proliferation associated with slitlike vessels, dermal fibrosis, and marked cellularity with nuclear atypia (H&E, original magnification ×200).

Figure 6. Spindled cells reactive to human herpesvirus 8 immunostain (original magnification ×400).

In summary, we present 2 cases of non–HIV-related KS that may represent an additional clinical variant of KS that mimics and/or arises in chronic venous insufficiency and appears as papules and plaques in elderly patients who are Hispanic, immunocompetent, and HIV negative. We suggest including KS in the differential diagnosis for chronic venous insufficiency, especially in cases with an unusual clinical appearance or course. In these cases, skin biopsy with HHV-8 testing may be warranted.

Acknowledgment

The authors would like to acknowledge William Putnam, BFA, New York, New York, for his assistance with the figures.

The Diagnosis: Pancreatic Panniculitis

The biopsy specimen revealed necrosis of the panniculus with “ghost” cells (Figure). Calcification was encountered. Changes of vasculitis were not identified and fungal organisms were not noted. The histopathologic findings supported a diagnosis of pancreatic panniculitis.

Punch biopsy revealed necrosis of the panniculus with “ghost” cells, and calcification was encountered (H&E, original magnification ×20).

Pancreatic panniculitis has been associated with pancreatitis, pancreatic carcinoma, pancreatic pseudocysts, congenital abnormalities of the pancreas, and drug-induced pancreatitis.¹ Skin lesions may herald a diagnosis of pancreatic disease in an outpatient and should prompt thorough clinical evaluation when encountered in an outpatient setting. Our patient first developed tender nodules on the left shin 2 to 3 weeks prior to presentation. She reported that her initial nodules were flesh colored but then became erythematous and tender over 1 week’s time. The patient’s history was remarkable for ovarian cancer. She had been hospitalized 2 weeks prior to presentation for abdominal pain and ascites. Imaging studies revealed a cystic lesion in the head of the pancreas. The pancreas was traumatized during a peritoneal tap. Her nodules developed shortly thereafter and were distributed on the arms, legs, back, and abdomen.

Pancreatic tumors or inflammation are thought to trigger pancreatic panniculitis by releasing enzymes. Pancreatic enzymes such as lipase are thought to play a role in the development of pancreatic panniculitis by entering the vascular system and leading to fat necrosis.^2,3 Biopsy reveals necrosis of adipocytes in the center of fat lobules.⁴ Ghost cells result from hydrolytic activity of enzymes on the fat cells followed by calcium deposition. A report indicates that fungal infection or gout also can cause changes that mimic pancreatic panniculitis.⁵

Other entities in the differential diagnosis can be excluded by biopsy. Polyarteritis nodosa is a vasculitis. Although panniculitis may be seen in polyarteritis as a secondary phenomenon, lesions are centered around blood vessels and often eventuate in ulceration.⁶ Subcutaneous fungal infection typically reveals organisms on periodic acid–Schiff stain.⁷ Pyoderma gangrenosum is associated with ulceration and a neutrophilic infiltrate that is often centered around a central pilosebaceous unit in developing lesions.⁸ Erythema nodosum is a panniculitis in which septal inflammation predominates.⁹ These differential diagnoses of pancreatic panniculitis are summarized in the Table.

Pancreatic panniculitis can be associated with acute arthritis and inflammation of periarticular fat.¹⁰ Treatment of pancreatic panniculitis is usually focused on the underlying pancreatic disease.^11,12 Our patient benefited from analgesic therapy and her lesions improved on follow-up. Clinicians encountering a patient with new tender nodules should be prompted to perform a biopsy. When histopathologic evaluation reveals ghosted adipocytes, pancreatic panniculitis should be suspected and clinical evaluation undertaken.

The Diagnosis: Pancreatic Panniculitis

The biopsy specimen revealed necrosis of the panniculus with “ghost” cells (Figure). Calcification was encountered. Changes of vasculitis were not identified and fungal organisms were not noted. The histopathologic findings supported a diagnosis of pancreatic panniculitis.

Punch biopsy revealed necrosis of the panniculus with “ghost” cells, and calcification was encountered (H&E, original magnification ×20).

Pancreatic panniculitis has been associated with pancreatitis, pancreatic carcinoma, pancreatic pseudocysts, congenital abnormalities of the pancreas, and drug-induced pancreatitis.¹ Skin lesions may herald a diagnosis of pancreatic disease in an outpatient and should prompt thorough clinical evaluation when encountered in an outpatient setting. Our patient first developed tender nodules on the left shin 2 to 3 weeks prior to presentation. She reported that her initial nodules were flesh colored but then became erythematous and tender over 1 week’s time. The patient’s history was remarkable for ovarian cancer. She had been hospitalized 2 weeks prior to presentation for abdominal pain and ascites. Imaging studies revealed a cystic lesion in the head of the pancreas. The pancreas was traumatized during a peritoneal tap. Her nodules developed shortly thereafter and were distributed on the arms, legs, back, and abdomen.

Pancreatic tumors or inflammation are thought to trigger pancreatic panniculitis by releasing enzymes. Pancreatic enzymes such as lipase are thought to play a role in the development of pancreatic panniculitis by entering the vascular system and leading to fat necrosis.^2,3 Biopsy reveals necrosis of adipocytes in the center of fat lobules.⁴ Ghost cells result from hydrolytic activity of enzymes on the fat cells followed by calcium deposition. A report indicates that fungal infection or gout also can cause changes that mimic pancreatic panniculitis.⁵

Other entities in the differential diagnosis can be excluded by biopsy. Polyarteritis nodosa is a vasculitis. Although panniculitis may be seen in polyarteritis as a secondary phenomenon, lesions are centered around blood vessels and often eventuate in ulceration.⁶ Subcutaneous fungal infection typically reveals organisms on periodic acid–Schiff stain.⁷ Pyoderma gangrenosum is associated with ulceration and a neutrophilic infiltrate that is often centered around a central pilosebaceous unit in developing lesions.⁸ Erythema nodosum is a panniculitis in which septal inflammation predominates.⁹ These differential diagnoses of pancreatic panniculitis are summarized in the Table.

Pancreatic panniculitis can be associated with acute arthritis and inflammation of periarticular fat.¹⁰ Treatment of pancreatic panniculitis is usually focused on the underlying pancreatic disease.^11,12 Our patient benefited from analgesic therapy and her lesions improved on follow-up. Clinicians encountering a patient with new tender nodules should be prompted to perform a biopsy. When histopathologic evaluation reveals ghosted adipocytes, pancreatic panniculitis should be suspected and clinical evaluation undertaken.

The Diagnosis: Pancreatic Panniculitis

The biopsy specimen revealed necrosis of the panniculus with “ghost” cells (Figure). Calcification was encountered. Changes of vasculitis were not identified and fungal organisms were not noted. The histopathologic findings supported a diagnosis of pancreatic panniculitis.

Punch biopsy revealed necrosis of the panniculus with “ghost” cells, and calcification was encountered (H&E, original magnification ×20).

Pancreatic panniculitis has been associated with pancreatitis, pancreatic carcinoma, pancreatic pseudocysts, congenital abnormalities of the pancreas, and drug-induced pancreatitis.¹ Skin lesions may herald a diagnosis of pancreatic disease in an outpatient and should prompt thorough clinical evaluation when encountered in an outpatient setting. Our patient first developed tender nodules on the left shin 2 to 3 weeks prior to presentation. She reported that her initial nodules were flesh colored but then became erythematous and tender over 1 week’s time. The patient’s history was remarkable for ovarian cancer. She had been hospitalized 2 weeks prior to presentation for abdominal pain and ascites. Imaging studies revealed a cystic lesion in the head of the pancreas. The pancreas was traumatized during a peritoneal tap. Her nodules developed shortly thereafter and were distributed on the arms, legs, back, and abdomen.

Pancreatic tumors or inflammation are thought to trigger pancreatic panniculitis by releasing enzymes. Pancreatic enzymes such as lipase are thought to play a role in the development of pancreatic panniculitis by entering the vascular system and leading to fat necrosis.^2,3 Biopsy reveals necrosis of adipocytes in the center of fat lobules.⁴ Ghost cells result from hydrolytic activity of enzymes on the fat cells followed by calcium deposition. A report indicates that fungal infection or gout also can cause changes that mimic pancreatic panniculitis.⁵

Other entities in the differential diagnosis can be excluded by biopsy. Polyarteritis nodosa is a vasculitis. Although panniculitis may be seen in polyarteritis as a secondary phenomenon, lesions are centered around blood vessels and often eventuate in ulceration.⁶ Subcutaneous fungal infection typically reveals organisms on periodic acid–Schiff stain.⁷ Pyoderma gangrenosum is associated with ulceration and a neutrophilic infiltrate that is often centered around a central pilosebaceous unit in developing lesions.⁸ Erythema nodosum is a panniculitis in which septal inflammation predominates.⁹ These differential diagnoses of pancreatic panniculitis are summarized in the Table.

Pancreatic panniculitis can be associated with acute arthritis and inflammation of periarticular fat.¹⁰ Treatment of pancreatic panniculitis is usually focused on the underlying pancreatic disease.^11,12 Our patient benefited from analgesic therapy and her lesions improved on follow-up. Clinicians encountering a patient with new tender nodules should be prompted to perform a biopsy. When histopathologic evaluation reveals ghosted adipocytes, pancreatic panniculitis should be suspected and clinical evaluation undertaken.

Drug-induced lupus accounts for up to 10% of lupus erythematosus cases. Subacute cutaneous lupus erythematosus (SCLE) is a distinct clinical variant of lupus erythematosus that typically presents as annular, often scaly, erythematous plaques in photodistributed areas. Subacute cutaneous lupus erythematosus has been reported in association with multiple systemic medications including docetaxel, terbinafine, leuprolide acetate, etanercept, and efalizumab^1-5; however, the induction of SCLE by topical agents has not been widely reported. We report a case of local induction of lesions that clinically and histologically resembled SCLE in a 50-year-old woman following treatment with topical imiquimod.

Case Report

A 50-year-old woman presented with an adverse inflammatory reaction on the right side of the upper chest secondary to application of topical imiquimod. Prior to the current presentation the patient was diagnosed with a biopsy-proven superficial basal cell carcinoma (BCC) on the sun-exposed area of the upper right breast, and topical imiquimod therapy was initiated. Several days after starting treatment, the patient began applying imiquimod on areas of clinically normal skin on the upper chest as advised by her dermatologist. After 7 to 10 days of application the patient reported intense erythema, pain, and crusting in the treated area on the right side of the upper chest. She also experienced systemic symptoms including fatigue, arthralgia, malaise, and fever.

Clinical examination revealed erythematous to violaceous annular and polycyclic plaques on the upper chest (Figure 1). Erythema and scaling were noted at the site of the superficial BCC. A biopsy showed a superficial and mid-dermal perivascular and periadnexal lymphocytic infiltrate with overlying vacuolar interface dermatitis and scattered necrotic keratinocytes (Figures 2A and 2B). There was slightly increased dermal edema and mucin. Anti-CD123 immunohistochemical staining revealed nodular aggregates of plasmacytoid dendritic cells (pDCs) accompanying lymphocytes around dermal vessels and adnexa (Figure 2C). The patient’s family history was remarkable for SCLE in her daughter. Antinuclear antibody, anti-Ro (Sjögren syndrome antigen A), and anti-La (Sjögren syndrome antigen B) were negative. On follow-up examination 1 month after discontinuation of imiquimod, the patient’s skin lesions had completely cleared. Two years later, the patient continued to be free of skin lesions.

Figure 1. Annular plaques on the upper chest with overlying scale and focal central clearing.

Figure 2. Vacuolar interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (A)(H&E, original magnification ×40). Scattered necrotic keratinocytes were evident (B)(H&E, original magnification ×400). Anti-CD123 immunohistochemical staining revealed nodular aggregates of plasmacytoid dendritic cells with accompanying lymphocytes centered around dermal vessels and adnexa (C)(original magnification ×200).

Comment

Imiquimod is a topical immunomodulator used for the treatment of genital warts and cutaneous malignancies. It exerts its effect via induction of proinflammatory cytokines (eg, IFN-a, tumor necrosis factor a [TNF-α]) through activation of toll-like receptor (TLR) 7, an intracytoplasmic receptor that is found on several cell types including pDCs and B cells. When the cell surface receptor is bound by activating ligands (eg, single-stranded RNA, imiquimod), downstream signaling is initiated, resulting in the production of large amounts of IFN-a and TNF-α.^6,7 Both IFN-a and TNF-α are upregulated in patient serum and lesional skin in SCLE.^8,9 Additionally, pDCs have been shown to accumulate in lesions of cutaneous lupus erythematosus (CLE) in a distinct dermal pattern, as demonstrated by CD123 staining.^9,10 This pattern is identical to the one seen in our case. Although pDCs also are present in cutaneous dermatomyositis lesions, the pattern is distinct from CLE.¹⁰ These findings indicate that IFN-a produced by pDCs may play an integral role in the pathogenesis of CLE. Several observations implicating TLR signaling in the pathogenesis of lupus have been described. In a lupus-prone mouse model of lupus erythematosus, transgenic overexpression of TLR-7 resulted in increased severity of clinical disease and accelerated mortality. Antimalarials improve lupus erythematosus via blockade of TLR-7 and TLR-9 signaling.¹¹

Imiquimod, which acts as an inducer of IFN-α expression through TLR-7 signaling, may have been an inciting factor in the development of SCLE-like lesions in this genetically predisposed patient. Histopathology of cutaneous malignancies treated with topical imiquimod typically does not show lupuslike features.¹² It is possible that a subset of predisposed patients have increased numbers of pDCs primed in their skin or that they exhibit a more robust TLR-7 reaction to imiquimod, resulting in abundant IFN-a production. Other autoimmune diseases, such as pemphigus foliaceus and vitiligo, also have been reported to occur locally after the application of imiquimod,^13,14 which suggests that a localized autoimmune reaction can be induced by activation of TLR-7; however, a case of chronic discoid lupus erythematosus of the scalp improving after treatment with imiquimod has been reported.¹⁵

The use of imiquimod in patients with a personal or family history of lupus erythematosus or those with a personal history of an autoimmune blistering disorder should be undertaken with caution until more is known.

Drug-induced lupus accounts for up to 10% of lupus erythematosus cases. Subacute cutaneous lupus erythematosus (SCLE) is a distinct clinical variant of lupus erythematosus that typically presents as annular, often scaly, erythematous plaques in photodistributed areas. Subacute cutaneous lupus erythematosus has been reported in association with multiple systemic medications including docetaxel, terbinafine, leuprolide acetate, etanercept, and efalizumab^1-5; however, the induction of SCLE by topical agents has not been widely reported. We report a case of local induction of lesions that clinically and histologically resembled SCLE in a 50-year-old woman following treatment with topical imiquimod.

Case Report

A 50-year-old woman presented with an adverse inflammatory reaction on the right side of the upper chest secondary to application of topical imiquimod. Prior to the current presentation the patient was diagnosed with a biopsy-proven superficial basal cell carcinoma (BCC) on the sun-exposed area of the upper right breast, and topical imiquimod therapy was initiated. Several days after starting treatment, the patient began applying imiquimod on areas of clinically normal skin on the upper chest as advised by her dermatologist. After 7 to 10 days of application the patient reported intense erythema, pain, and crusting in the treated area on the right side of the upper chest. She also experienced systemic symptoms including fatigue, arthralgia, malaise, and fever.

Clinical examination revealed erythematous to violaceous annular and polycyclic plaques on the upper chest (Figure 1). Erythema and scaling were noted at the site of the superficial BCC. A biopsy showed a superficial and mid-dermal perivascular and periadnexal lymphocytic infiltrate with overlying vacuolar interface dermatitis and scattered necrotic keratinocytes (Figures 2A and 2B). There was slightly increased dermal edema and mucin. Anti-CD123 immunohistochemical staining revealed nodular aggregates of plasmacytoid dendritic cells (pDCs) accompanying lymphocytes around dermal vessels and adnexa (Figure 2C). The patient’s family history was remarkable for SCLE in her daughter. Antinuclear antibody, anti-Ro (Sjögren syndrome antigen A), and anti-La (Sjögren syndrome antigen B) were negative. On follow-up examination 1 month after discontinuation of imiquimod, the patient’s skin lesions had completely cleared. Two years later, the patient continued to be free of skin lesions.

Figure 1. Annular plaques on the upper chest with overlying scale and focal central clearing.

Figure 2. Vacuolar interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (A)(H&E, original magnification ×40). Scattered necrotic keratinocytes were evident (B)(H&E, original magnification ×400). Anti-CD123 immunohistochemical staining revealed nodular aggregates of plasmacytoid dendritic cells with accompanying lymphocytes centered around dermal vessels and adnexa (C)(original magnification ×200).

Comment

Imiquimod is a topical immunomodulator used for the treatment of genital warts and cutaneous malignancies. It exerts its effect via induction of proinflammatory cytokines (eg, IFN-a, tumor necrosis factor a [TNF-α]) through activation of toll-like receptor (TLR) 7, an intracytoplasmic receptor that is found on several cell types including pDCs and B cells. When the cell surface receptor is bound by activating ligands (eg, single-stranded RNA, imiquimod), downstream signaling is initiated, resulting in the production of large amounts of IFN-a and TNF-α.^6,7 Both IFN-a and TNF-α are upregulated in patient serum and lesional skin in SCLE.^8,9 Additionally, pDCs have been shown to accumulate in lesions of cutaneous lupus erythematosus (CLE) in a distinct dermal pattern, as demonstrated by CD123 staining.^9,10 This pattern is identical to the one seen in our case. Although pDCs also are present in cutaneous dermatomyositis lesions, the pattern is distinct from CLE.¹⁰ These findings indicate that IFN-a produced by pDCs may play an integral role in the pathogenesis of CLE. Several observations implicating TLR signaling in the pathogenesis of lupus have been described. In a lupus-prone mouse model of lupus erythematosus, transgenic overexpression of TLR-7 resulted in increased severity of clinical disease and accelerated mortality. Antimalarials improve lupus erythematosus via blockade of TLR-7 and TLR-9 signaling.¹¹

Imiquimod, which acts as an inducer of IFN-α expression through TLR-7 signaling, may have been an inciting factor in the development of SCLE-like lesions in this genetically predisposed patient. Histopathology of cutaneous malignancies treated with topical imiquimod typically does not show lupuslike features.¹² It is possible that a subset of predisposed patients have increased numbers of pDCs primed in their skin or that they exhibit a more robust TLR-7 reaction to imiquimod, resulting in abundant IFN-a production. Other autoimmune diseases, such as pemphigus foliaceus and vitiligo, also have been reported to occur locally after the application of imiquimod,^13,14 which suggests that a localized autoimmune reaction can be induced by activation of TLR-7; however, a case of chronic discoid lupus erythematosus of the scalp improving after treatment with imiquimod has been reported.¹⁵

The use of imiquimod in patients with a personal or family history of lupus erythematosus or those with a personal history of an autoimmune blistering disorder should be undertaken with caution until more is known.

Drug-induced lupus accounts for up to 10% of lupus erythematosus cases. Subacute cutaneous lupus erythematosus (SCLE) is a distinct clinical variant of lupus erythematosus that typically presents as annular, often scaly, erythematous plaques in photodistributed areas. Subacute cutaneous lupus erythematosus has been reported in association with multiple systemic medications including docetaxel, terbinafine, leuprolide acetate, etanercept, and efalizumab^1-5; however, the induction of SCLE by topical agents has not been widely reported. We report a case of local induction of lesions that clinically and histologically resembled SCLE in a 50-year-old woman following treatment with topical imiquimod.

Case Report

A 50-year-old woman presented with an adverse inflammatory reaction on the right side of the upper chest secondary to application of topical imiquimod. Prior to the current presentation the patient was diagnosed with a biopsy-proven superficial basal cell carcinoma (BCC) on the sun-exposed area of the upper right breast, and topical imiquimod therapy was initiated. Several days after starting treatment, the patient began applying imiquimod on areas of clinically normal skin on the upper chest as advised by her dermatologist. After 7 to 10 days of application the patient reported intense erythema, pain, and crusting in the treated area on the right side of the upper chest. She also experienced systemic symptoms including fatigue, arthralgia, malaise, and fever.

Clinical examination revealed erythematous to violaceous annular and polycyclic plaques on the upper chest (Figure 1). Erythema and scaling were noted at the site of the superficial BCC. A biopsy showed a superficial and mid-dermal perivascular and periadnexal lymphocytic infiltrate with overlying vacuolar interface dermatitis and scattered necrotic keratinocytes (Figures 2A and 2B). There was slightly increased dermal edema and mucin. Anti-CD123 immunohistochemical staining revealed nodular aggregates of plasmacytoid dendritic cells (pDCs) accompanying lymphocytes around dermal vessels and adnexa (Figure 2C). The patient’s family history was remarkable for SCLE in her daughter. Antinuclear antibody, anti-Ro (Sjögren syndrome antigen A), and anti-La (Sjögren syndrome antigen B) were negative. On follow-up examination 1 month after discontinuation of imiquimod, the patient’s skin lesions had completely cleared. Two years later, the patient continued to be free of skin lesions.

Figure 1. Annular plaques on the upper chest with overlying scale and focal central clearing.

Figure 2. Vacuolar interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (A)(H&E, original magnification ×40). Scattered necrotic keratinocytes were evident (B)(H&E, original magnification ×400). Anti-CD123 immunohistochemical staining revealed nodular aggregates of plasmacytoid dendritic cells with accompanying lymphocytes centered around dermal vessels and adnexa (C)(original magnification ×200).

Comment

Imiquimod is a topical immunomodulator used for the treatment of genital warts and cutaneous malignancies. It exerts its effect via induction of proinflammatory cytokines (eg, IFN-a, tumor necrosis factor a [TNF-α]) through activation of toll-like receptor (TLR) 7, an intracytoplasmic receptor that is found on several cell types including pDCs and B cells. When the cell surface receptor is bound by activating ligands (eg, single-stranded RNA, imiquimod), downstream signaling is initiated, resulting in the production of large amounts of IFN-a and TNF-α.^6,7 Both IFN-a and TNF-α are upregulated in patient serum and lesional skin in SCLE.^8,9 Additionally, pDCs have been shown to accumulate in lesions of cutaneous lupus erythematosus (CLE) in a distinct dermal pattern, as demonstrated by CD123 staining.^9,10 This pattern is identical to the one seen in our case. Although pDCs also are present in cutaneous dermatomyositis lesions, the pattern is distinct from CLE.¹⁰ These findings indicate that IFN-a produced by pDCs may play an integral role in the pathogenesis of CLE. Several observations implicating TLR signaling in the pathogenesis of lupus have been described. In a lupus-prone mouse model of lupus erythematosus, transgenic overexpression of TLR-7 resulted in increased severity of clinical disease and accelerated mortality. Antimalarials improve lupus erythematosus via blockade of TLR-7 and TLR-9 signaling.¹¹

Imiquimod, which acts as an inducer of IFN-α expression through TLR-7 signaling, may have been an inciting factor in the development of SCLE-like lesions in this genetically predisposed patient. Histopathology of cutaneous malignancies treated with topical imiquimod typically does not show lupuslike features.¹² It is possible that a subset of predisposed patients have increased numbers of pDCs primed in their skin or that they exhibit a more robust TLR-7 reaction to imiquimod, resulting in abundant IFN-a production. Other autoimmune diseases, such as pemphigus foliaceus and vitiligo, also have been reported to occur locally after the application of imiquimod,^13,14 which suggests that a localized autoimmune reaction can be induced by activation of TLR-7; however, a case of chronic discoid lupus erythematosus of the scalp improving after treatment with imiquimod has been reported.¹⁵

The use of imiquimod in patients with a personal or family history of lupus erythematosus or those with a personal history of an autoimmune blistering disorder should be undertaken with caution until more is known.

Leukemia cutis (LC) is characterized by the infiltration of malignant neoplastic leukocytes or their precursors into the skin, most often in conjunction with systemic leukemia.¹ Acute myelogenous leukemia (AML) is the second most common cause of LC and the most common form of leukemia among adults.¹ Patients with leukemia often are in a relative or absolute immunocompromised state, which may be secondary to neutropenia, chemotherapy regimens, or immunosuppressive regimens following stem cell transplant (SCT). Thus, when evaluating cutaneous lesions consistent with LC in immunocompromised patients, there must be a high index of suspicion for concomitant opportunistic infections.

We report the case of a 52-year-old man with primary refractory AML following allogeneic SCT with relapse who presented with an LC lesion below the knee with concomitant invasive fungal infection despite being on prophylactic oral antifungal therapy.

Case Report

A 52-year-old man with primary refractory AML (M1) of 1 year’s duration presented for evaluation of a slowly progressing reddish purple nodule on the right knee of 2 to 4 months’ duration. The patient had undergone a matched unrelated donor allogeneic SCT 6 months following diagnosis of AML with subsequent disease progression despite reduction of posttransplant graft-versus-host disease prophylactic immune suppression and a cycle of clofarabine. The patient was hospitalized 2 months after the SCT for neutropenic fever and was found to have vancomycin-resistant enterococcal bacteremia, Clostridium difficile colitis, and possible fungal pneumonia. He was treated with voriconazole 200 mg twice daily, which he continued following discharge for antifungal prophylaxis. At the time of discharge, the patient reported that he noticed an asymptomatic “purple papule” on the right knee but did not seek further workup.

Two months later, the patient presented with a fever (temperature, 38.6°C) and leukocytosis (white blood cell count, 130 cells/mL [increased from 53 cells/mL 1 week prior to admission]). Due to his history of immunosuppression and neutropenia, the patient was placed on a broad-spectrum antibiotic regimen of cefepime, daptomycin, and linezolid on admission. Later, vancomycin and gentamicin were added and voriconazole was switched to caspofungin. The patient also received granulocyte-macrophage colony-stimulating factor for neutropenia. During the current hospitalization, blood cultures demonstrated vancomycin-resistant enterococcemia, and computed tomography of the chest revealed findings consistent with multilobar pneumonia.

Figure 1. A large round, reddish purple, centrally ulcerated plaque with dark hemorrhagic crust and a surrounding patch of erythema inferior to the knee on the right lateral lower leg.

Dermatology was consulted to evaluate the purple nodule on the right knee, which had slowly progressed since his last admission. Physical examination revealed a violaceous, 1.5×1.5-cm nodule with central necrosis covered by black eschar with surrounding erythema (Figure 1). Biopsy specimens for routine histology and a tissue culture were obtained. Histopathologic examination revealed a dense diffuse infiltrate of large hyperchromatic mononuclear cells extending through the dermis, which was consistent with the patient’s known AML (Figure 2). Acid-fast bacillus staining was negative for mycobacterial organisms. Grocott-Gomori methenamine-silver stain demonstrated an overwhelming number of septate fungal hyphae with acute-angle branching, concerning for Aspergillus species (Figure 3). Of note, an Aspergillus serum antigen test was performed at this time and was negative. On repeat review of the routine histologic sections, angioinvasion by hyphae was detected amidst the dense lymphocytic infiltrate (Figure 4).

Given the patient’s immunocompromised state, the presence of angioinvasive fungi on the skin biopsy, and unresolved pneumonia, the patient was restarted on voriconazole for treatment of likely Aspergillus infection. He was continued on chemotherapy for the primary refractory AML and received a donor lymphocyte infusion prior to discharge. After the patient was discharged, the tissue culture grew Paecilomyces, a rare fungal species. The patient died 1 week after discharge.

Figure 2. A punch biopsy specimen demonstrated a dense interstitial infiltrate of hyperchromatic cells extending through the dermis (A)(H&E, original magnification ×200). Higher-power view of monomorphic cells exhibited elevated nuclear-cytoplasmic ratios (B)(H&E, original magnification ×600).

Figure 3. Grocott-Gomori methenamine-silver stain revealed numerous fungal hyphae (A)(original magnification ×200). Higher-power magnification showed septate fungal hyphae (B)(original magnification ×600).

Figure 4. Leukemia cutis and numerous fungal hyphae demonstrated angioinvasion (H&E, original magnification ×200).

Comment

Leukemia cutis is an extramedullary manifestation of leukemia that appears in 10% to 15% of patients with AML.² The frequency of LC differs widely for the various types of AML, with the majority of cases occurring in the acute myelomonocytic leukemia (M4) or acute monocytic leukemia (M5) subtypes.^3,4 One large study of AML patients (N=381) demonstrated an incidence of LC in 28.6% of patients with the M4 subtype and 42.9% of those with the M5 subtype, with an incidence of only 7.1% of patients with the M1 subtype.³ It occurs less frequently in chronic myeloproliferative diseases.^2,4

Leukemia cutis has a wide range of cutaneous manifestations and may present with solitary or multiple papular, nodular, or plaquelike lesions that are red-brown, blue, violaceous, or hemorrhagic.⁴ Leukemia cutis occurs most commonly on the legs, followed by the arms, back, chest, scalp, and face.^2,4 Leukemia cutis may be hard to distinguish clinically from other conditions such as cutaneous metastases of visceral malignancies, lymphoma, drug eruptions, and opportunistic infections. Leukemia cutis ulcers often measure only a few centimeters in diameter with a firmly adherent purulent or hemorrhagic crust and may occur in unusual locations. These lesions usually are treatment resistant and their persistence may help to lead to diagnosis.⁴

Microscopically, most LC lesions show a perivascular or periadnexal pattern of involvement or a dense diffuse, interstitial, or nodular atypical lymphocytic infiltrate involving the dermis and subcutis with sparing of the upper papillary dermis.² The cytologic appearance of M1 and M2 subtypes of AML are characterized by medium-sized to large mononuclear cells with a light cytoplasm and large basophilic cell nuclei. The M4 and M5 subtypes of AML generally are dominated by medium-sized, round or oval-shaped mononuclear cells that may have eosinophilic cytoplasm and segmented or kidney-shaped basophilic nuclei.⁴ Immunophenotyping is crucial for diagnosis. In myeloid disorders, there is positive staining with markers of myeloid lineage such as myeloperoxidase, lysozyme, CD34, CD15, CD68, CD43, and CD117.⁵

In our patient, there was an ulcerated dense diffuse dermal infiltrate of large atypical lymphocytes consistent with LC and positive immunostaining consistent with LC associated with AML. Additionally, septate hyphae with acute-angle branching also were noted in the dermal blood vessels on hematoxylin and eosin and fungal staining, demonstrating concomitant fungal infection. Angioinvasion of organisms demonstrated on skin biopsy and persistent pneumonia noted on chest imaging suggested a disseminated infectious process.       

Invasive fungal infections are an increasing cause of morbidity and mortality in immunocompromised individuals, including those with hematologic malignancies and hematologic SCTs. Despite an increasing number of antifungal therapies, outcomes are frequently suboptimal with mortality rates often greater than 50% depending on the pathogen and disease.⁶ Thus, there must be a high index of suspicion of infection even when a separate histopathologic diagnosis is available, such as the finding of leukemic infiltrates in this patient’s biopsy specimen. A similar case of LC has been reported with concomitant fungal infection involving Fusarium and Enterococcus.⁷ Patients with leukemic cells may develop leukemic infiltrates in response to cutaneous infection, and a high index of suspicion for 2 related but distinct processes is necessary.

Paecilomyces species are an emerging cause of opportunistic and usually severe human infections.^8-11 The Paecilomyces species are saprophytic filamentous fungi that are found worldwide in soil as well as contaminants in the air and water.¹²Paecilomyces infection is generally associated with the use of immunosuppressive therapies, implants, or ocular surgery. Among species in this genus, Paecilomyces lilacinus and Paecilomyces variotii are of clinical importance. Most species have high susceptibility to the newer azoles such as voriconazole.⁶

Conclusion

Despite continued treatment with voriconazole, our patient still developed a rare fungal infection arising in a lesion of LC. He had signs of infection, including an elevated white blood cell count, fever, and malaise, which are nonspecific clinical findings that could have been attributed to known relapse of systemic leukemia or to known enterococcemia. Even in patients on antifungal prophylaxis and with other possible causes of leukocytosis, this case illustrates that there must be a high index of suspicion for angioinvasive fungal infection.

Leukemia cutis (LC) is characterized by the infiltration of malignant neoplastic leukocytes or their precursors into the skin, most often in conjunction with systemic leukemia.¹ Acute myelogenous leukemia (AML) is the second most common cause of LC and the most common form of leukemia among adults.¹ Patients with leukemia often are in a relative or absolute immunocompromised state, which may be secondary to neutropenia, chemotherapy regimens, or immunosuppressive regimens following stem cell transplant (SCT). Thus, when evaluating cutaneous lesions consistent with LC in immunocompromised patients, there must be a high index of suspicion for concomitant opportunistic infections.

We report the case of a 52-year-old man with primary refractory AML following allogeneic SCT with relapse who presented with an LC lesion below the knee with concomitant invasive fungal infection despite being on prophylactic oral antifungal therapy.

Case Report

A 52-year-old man with primary refractory AML (M1) of 1 year’s duration presented for evaluation of a slowly progressing reddish purple nodule on the right knee of 2 to 4 months’ duration. The patient had undergone a matched unrelated donor allogeneic SCT 6 months following diagnosis of AML with subsequent disease progression despite reduction of posttransplant graft-versus-host disease prophylactic immune suppression and a cycle of clofarabine. The patient was hospitalized 2 months after the SCT for neutropenic fever and was found to have vancomycin-resistant enterococcal bacteremia, Clostridium difficile colitis, and possible fungal pneumonia. He was treated with voriconazole 200 mg twice daily, which he continued following discharge for antifungal prophylaxis. At the time of discharge, the patient reported that he noticed an asymptomatic “purple papule” on the right knee but did not seek further workup.

Two months later, the patient presented with a fever (temperature, 38.6°C) and leukocytosis (white blood cell count, 130 cells/mL [increased from 53 cells/mL 1 week prior to admission]). Due to his history of immunosuppression and neutropenia, the patient was placed on a broad-spectrum antibiotic regimen of cefepime, daptomycin, and linezolid on admission. Later, vancomycin and gentamicin were added and voriconazole was switched to caspofungin. The patient also received granulocyte-macrophage colony-stimulating factor for neutropenia. During the current hospitalization, blood cultures demonstrated vancomycin-resistant enterococcemia, and computed tomography of the chest revealed findings consistent with multilobar pneumonia.

Figure 1. A large round, reddish purple, centrally ulcerated plaque with dark hemorrhagic crust and a surrounding patch of erythema inferior to the knee on the right lateral lower leg.

Dermatology was consulted to evaluate the purple nodule on the right knee, which had slowly progressed since his last admission. Physical examination revealed a violaceous, 1.5×1.5-cm nodule with central necrosis covered by black eschar with surrounding erythema (Figure 1). Biopsy specimens for routine histology and a tissue culture were obtained. Histopathologic examination revealed a dense diffuse infiltrate of large hyperchromatic mononuclear cells extending through the dermis, which was consistent with the patient’s known AML (Figure 2). Acid-fast bacillus staining was negative for mycobacterial organisms. Grocott-Gomori methenamine-silver stain demonstrated an overwhelming number of septate fungal hyphae with acute-angle branching, concerning for Aspergillus species (Figure 3). Of note, an Aspergillus serum antigen test was performed at this time and was negative. On repeat review of the routine histologic sections, angioinvasion by hyphae was detected amidst the dense lymphocytic infiltrate (Figure 4).

Given the patient’s immunocompromised state, the presence of angioinvasive fungi on the skin biopsy, and unresolved pneumonia, the patient was restarted on voriconazole for treatment of likely Aspergillus infection. He was continued on chemotherapy for the primary refractory AML and received a donor lymphocyte infusion prior to discharge. After the patient was discharged, the tissue culture grew Paecilomyces, a rare fungal species. The patient died 1 week after discharge.

Figure 2. A punch biopsy specimen demonstrated a dense interstitial infiltrate of hyperchromatic cells extending through the dermis (A)(H&E, original magnification ×200). Higher-power view of monomorphic cells exhibited elevated nuclear-cytoplasmic ratios (B)(H&E, original magnification ×600).

Figure 3. Grocott-Gomori methenamine-silver stain revealed numerous fungal hyphae (A)(original magnification ×200). Higher-power magnification showed septate fungal hyphae (B)(original magnification ×600).

Figure 4. Leukemia cutis and numerous fungal hyphae demonstrated angioinvasion (H&E, original magnification ×200).

Comment

Leukemia cutis is an extramedullary manifestation of leukemia that appears in 10% to 15% of patients with AML.² The frequency of LC differs widely for the various types of AML, with the majority of cases occurring in the acute myelomonocytic leukemia (M4) or acute monocytic leukemia (M5) subtypes.^3,4 One large study of AML patients (N=381) demonstrated an incidence of LC in 28.6% of patients with the M4 subtype and 42.9% of those with the M5 subtype, with an incidence of only 7.1% of patients with the M1 subtype.³ It occurs less frequently in chronic myeloproliferative diseases.^2,4

Leukemia cutis has a wide range of cutaneous manifestations and may present with solitary or multiple papular, nodular, or plaquelike lesions that are red-brown, blue, violaceous, or hemorrhagic.⁴ Leukemia cutis occurs most commonly on the legs, followed by the arms, back, chest, scalp, and face.^2,4 Leukemia cutis may be hard to distinguish clinically from other conditions such as cutaneous metastases of visceral malignancies, lymphoma, drug eruptions, and opportunistic infections. Leukemia cutis ulcers often measure only a few centimeters in diameter with a firmly adherent purulent or hemorrhagic crust and may occur in unusual locations. These lesions usually are treatment resistant and their persistence may help to lead to diagnosis.⁴

Microscopically, most LC lesions show a perivascular or periadnexal pattern of involvement or a dense diffuse, interstitial, or nodular atypical lymphocytic infiltrate involving the dermis and subcutis with sparing of the upper papillary dermis.² The cytologic appearance of M1 and M2 subtypes of AML are characterized by medium-sized to large mononuclear cells with a light cytoplasm and large basophilic cell nuclei. The M4 and M5 subtypes of AML generally are dominated by medium-sized, round or oval-shaped mononuclear cells that may have eosinophilic cytoplasm and segmented or kidney-shaped basophilic nuclei.⁴ Immunophenotyping is crucial for diagnosis. In myeloid disorders, there is positive staining with markers of myeloid lineage such as myeloperoxidase, lysozyme, CD34, CD15, CD68, CD43, and CD117.⁵

In our patient, there was an ulcerated dense diffuse dermal infiltrate of large atypical lymphocytes consistent with LC and positive immunostaining consistent with LC associated with AML. Additionally, septate hyphae with acute-angle branching also were noted in the dermal blood vessels on hematoxylin and eosin and fungal staining, demonstrating concomitant fungal infection. Angioinvasion of organisms demonstrated on skin biopsy and persistent pneumonia noted on chest imaging suggested a disseminated infectious process.       

Invasive fungal infections are an increasing cause of morbidity and mortality in immunocompromised individuals, including those with hematologic malignancies and hematologic SCTs. Despite an increasing number of antifungal therapies, outcomes are frequently suboptimal with mortality rates often greater than 50% depending on the pathogen and disease.⁶ Thus, there must be a high index of suspicion of infection even when a separate histopathologic diagnosis is available, such as the finding of leukemic infiltrates in this patient’s biopsy specimen. A similar case of LC has been reported with concomitant fungal infection involving Fusarium and Enterococcus.⁷ Patients with leukemic cells may develop leukemic infiltrates in response to cutaneous infection, and a high index of suspicion for 2 related but distinct processes is necessary.

Paecilomyces species are an emerging cause of opportunistic and usually severe human infections.^8-11 The Paecilomyces species are saprophytic filamentous fungi that are found worldwide in soil as well as contaminants in the air and water.¹²Paecilomyces infection is generally associated with the use of immunosuppressive therapies, implants, or ocular surgery. Among species in this genus, Paecilomyces lilacinus and Paecilomyces variotii are of clinical importance. Most species have high susceptibility to the newer azoles such as voriconazole.⁶

Conclusion

Despite continued treatment with voriconazole, our patient still developed a rare fungal infection arising in a lesion of LC. He had signs of infection, including an elevated white blood cell count, fever, and malaise, which are nonspecific clinical findings that could have been attributed to known relapse of systemic leukemia or to known enterococcemia. Even in patients on antifungal prophylaxis and with other possible causes of leukocytosis, this case illustrates that there must be a high index of suspicion for angioinvasive fungal infection.

Leukemia cutis (LC) is characterized by the infiltration of malignant neoplastic leukocytes or their precursors into the skin, most often in conjunction with systemic leukemia.¹ Acute myelogenous leukemia (AML) is the second most common cause of LC and the most common form of leukemia among adults.¹ Patients with leukemia often are in a relative or absolute immunocompromised state, which may be secondary to neutropenia, chemotherapy regimens, or immunosuppressive regimens following stem cell transplant (SCT). Thus, when evaluating cutaneous lesions consistent with LC in immunocompromised patients, there must be a high index of suspicion for concomitant opportunistic infections.

We report the case of a 52-year-old man with primary refractory AML following allogeneic SCT with relapse who presented with an LC lesion below the knee with concomitant invasive fungal infection despite being on prophylactic oral antifungal therapy.

Case Report

A 52-year-old man with primary refractory AML (M1) of 1 year’s duration presented for evaluation of a slowly progressing reddish purple nodule on the right knee of 2 to 4 months’ duration. The patient had undergone a matched unrelated donor allogeneic SCT 6 months following diagnosis of AML with subsequent disease progression despite reduction of posttransplant graft-versus-host disease prophylactic immune suppression and a cycle of clofarabine. The patient was hospitalized 2 months after the SCT for neutropenic fever and was found to have vancomycin-resistant enterococcal bacteremia, Clostridium difficile colitis, and possible fungal pneumonia. He was treated with voriconazole 200 mg twice daily, which he continued following discharge for antifungal prophylaxis. At the time of discharge, the patient reported that he noticed an asymptomatic “purple papule” on the right knee but did not seek further workup.

Two months later, the patient presented with a fever (temperature, 38.6°C) and leukocytosis (white blood cell count, 130 cells/mL [increased from 53 cells/mL 1 week prior to admission]). Due to his history of immunosuppression and neutropenia, the patient was placed on a broad-spectrum antibiotic regimen of cefepime, daptomycin, and linezolid on admission. Later, vancomycin and gentamicin were added and voriconazole was switched to caspofungin. The patient also received granulocyte-macrophage colony-stimulating factor for neutropenia. During the current hospitalization, blood cultures demonstrated vancomycin-resistant enterococcemia, and computed tomography of the chest revealed findings consistent with multilobar pneumonia.

Figure 1. A large round, reddish purple, centrally ulcerated plaque with dark hemorrhagic crust and a surrounding patch of erythema inferior to the knee on the right lateral lower leg.

Dermatology was consulted to evaluate the purple nodule on the right knee, which had slowly progressed since his last admission. Physical examination revealed a violaceous, 1.5×1.5-cm nodule with central necrosis covered by black eschar with surrounding erythema (Figure 1). Biopsy specimens for routine histology and a tissue culture were obtained. Histopathologic examination revealed a dense diffuse infiltrate of large hyperchromatic mononuclear cells extending through the dermis, which was consistent with the patient’s known AML (Figure 2). Acid-fast bacillus staining was negative for mycobacterial organisms. Grocott-Gomori methenamine-silver stain demonstrated an overwhelming number of septate fungal hyphae with acute-angle branching, concerning for Aspergillus species (Figure 3). Of note, an Aspergillus serum antigen test was performed at this time and was negative. On repeat review of the routine histologic sections, angioinvasion by hyphae was detected amidst the dense lymphocytic infiltrate (Figure 4).

Given the patient’s immunocompromised state, the presence of angioinvasive fungi on the skin biopsy, and unresolved pneumonia, the patient was restarted on voriconazole for treatment of likely Aspergillus infection. He was continued on chemotherapy for the primary refractory AML and received a donor lymphocyte infusion prior to discharge. After the patient was discharged, the tissue culture grew Paecilomyces, a rare fungal species. The patient died 1 week after discharge.

Figure 2. A punch biopsy specimen demonstrated a dense interstitial infiltrate of hyperchromatic cells extending through the dermis (A)(H&E, original magnification ×200). Higher-power view of monomorphic cells exhibited elevated nuclear-cytoplasmic ratios (B)(H&E, original magnification ×600).

Figure 3. Grocott-Gomori methenamine-silver stain revealed numerous fungal hyphae (A)(original magnification ×200). Higher-power magnification showed septate fungal hyphae (B)(original magnification ×600).

Figure 4. Leukemia cutis and numerous fungal hyphae demonstrated angioinvasion (H&E, original magnification ×200).

Comment

Leukemia cutis is an extramedullary manifestation of leukemia that appears in 10% to 15% of patients with AML.² The frequency of LC differs widely for the various types of AML, with the majority of cases occurring in the acute myelomonocytic leukemia (M4) or acute monocytic leukemia (M5) subtypes.^3,4 One large study of AML patients (N=381) demonstrated an incidence of LC in 28.6% of patients with the M4 subtype and 42.9% of those with the M5 subtype, with an incidence of only 7.1% of patients with the M1 subtype.³ It occurs less frequently in chronic myeloproliferative diseases.^2,4

Leukemia cutis has a wide range of cutaneous manifestations and may present with solitary or multiple papular, nodular, or plaquelike lesions that are red-brown, blue, violaceous, or hemorrhagic.⁴ Leukemia cutis occurs most commonly on the legs, followed by the arms, back, chest, scalp, and face.^2,4 Leukemia cutis may be hard to distinguish clinically from other conditions such as cutaneous metastases of visceral malignancies, lymphoma, drug eruptions, and opportunistic infections. Leukemia cutis ulcers often measure only a few centimeters in diameter with a firmly adherent purulent or hemorrhagic crust and may occur in unusual locations. These lesions usually are treatment resistant and their persistence may help to lead to diagnosis.⁴

Microscopically, most LC lesions show a perivascular or periadnexal pattern of involvement or a dense diffuse, interstitial, or nodular atypical lymphocytic infiltrate involving the dermis and subcutis with sparing of the upper papillary dermis.² The cytologic appearance of M1 and M2 subtypes of AML are characterized by medium-sized to large mononuclear cells with a light cytoplasm and large basophilic cell nuclei. The M4 and M5 subtypes of AML generally are dominated by medium-sized, round or oval-shaped mononuclear cells that may have eosinophilic cytoplasm and segmented or kidney-shaped basophilic nuclei.⁴ Immunophenotyping is crucial for diagnosis. In myeloid disorders, there is positive staining with markers of myeloid lineage such as myeloperoxidase, lysozyme, CD34, CD15, CD68, CD43, and CD117.⁵

In our patient, there was an ulcerated dense diffuse dermal infiltrate of large atypical lymphocytes consistent with LC and positive immunostaining consistent with LC associated with AML. Additionally, septate hyphae with acute-angle branching also were noted in the dermal blood vessels on hematoxylin and eosin and fungal staining, demonstrating concomitant fungal infection. Angioinvasion of organisms demonstrated on skin biopsy and persistent pneumonia noted on chest imaging suggested a disseminated infectious process.       

Invasive fungal infections are an increasing cause of morbidity and mortality in immunocompromised individuals, including those with hematologic malignancies and hematologic SCTs. Despite an increasing number of antifungal therapies, outcomes are frequently suboptimal with mortality rates often greater than 50% depending on the pathogen and disease.⁶ Thus, there must be a high index of suspicion of infection even when a separate histopathologic diagnosis is available, such as the finding of leukemic infiltrates in this patient’s biopsy specimen. A similar case of LC has been reported with concomitant fungal infection involving Fusarium and Enterococcus.⁷ Patients with leukemic cells may develop leukemic infiltrates in response to cutaneous infection, and a high index of suspicion for 2 related but distinct processes is necessary.

Paecilomyces species are an emerging cause of opportunistic and usually severe human infections.^8-11 The Paecilomyces species are saprophytic filamentous fungi that are found worldwide in soil as well as contaminants in the air and water.¹²Paecilomyces infection is generally associated with the use of immunosuppressive therapies, implants, or ocular surgery. Among species in this genus, Paecilomyces lilacinus and Paecilomyces variotii are of clinical importance. Most species have high susceptibility to the newer azoles such as voriconazole.⁶

Conclusion

Despite continued treatment with voriconazole, our patient still developed a rare fungal infection arising in a lesion of LC. He had signs of infection, including an elevated white blood cell count, fever, and malaise, which are nonspecific clinical findings that could have been attributed to known relapse of systemic leukemia or to known enterococcemia. Even in patients on antifungal prophylaxis and with other possible causes of leukocytosis, this case illustrates that there must be a high index of suspicion for angioinvasive fungal infection.

Case Report

Clinical Findings

A 65-year-old woman presented with multiple asymptomatic discrete nodules and atrophic plaques on the thighs of 4 years’ duration. The lesions had started as 2 small, asymptomatic, madder red plaques symmetrically located on the anterior aspect of each thigh that had gradually increased in number and size, particularly on the right thigh. Two years later, 2 new atrophic plaques appeared on the anterior aspect of each. The lesions developed slowly but never remitted and had been misdiagnosed as primary macular atrophy of skin by several outpatient clinics. The patient’s general health was good and her personal and family history was unremarkable.

Physical examination revealed multiple madder red plaques and nodules of various shapes and sizes (ie, 1–3 cm in diameter) on the anterior aspect of the right thigh. The lesions were slightly elevated with a waxy surface, firm, and painless to palpation. One similar lesion was noted on the anterior aspect of the left thigh. Two 2-cm, brown-red, atrophic plaques also were noted in a symmetrical distribution on the anterior aspect of each thigh. The plaque surfaces were slightly crinkly and shiny, and anetodermalike lesions produced a buttonhole sign identical to a neurofibroma on palpation (Figure 1).

Figure 1. Multiple madder red plaques, nodules, and atrophic plaques in various shapes and sizes were seen on the anterior aspect of both thighs.

Histopathologic Findings

Two biopsy specimens were taken from a nodule and an atrophic plaque on the right thigh. Microscopic examination revealed deposition of homogeneous eosinophilic material in the reticular dermis and subcutis as well as around the fine vessels (Figure 2A). There was mild cellular infiltration of lymphocytes, plasma cells, and giant cells in the dermis, especially adjacent to deposits and around the vessels (Figure 2B). The homogeneous material appeared salmon pink on Congo red staining and bright green by thioflavin T staining using a fluorescent microscope (Figures 3 and 4). These results suggested the characteristic features of cutaneous nodular amyloidosis.

Figure 2. Histopathologically, homogeneous eosinophilic material deposited in the reticular dermis and subcutis was noted (A)(H&E, original magnification ×25). Microscopic examination showed lymphocytes and plasma cells infiltrated in the dermis, especially adjacent to deposits and around the vessels (B)(H&E, original magnification ×200).

Figure 3. Congo red staining showed salmon pink homogeneous material (original magnification ×25).

Figure 4. Thioflavin T staining showed bright green homogeneous material (original magnification ×100).

Laboratory Findings

Laboratory studies showed normal results for complete blood cell count, urinalysis, liver and renal function tests, blood glucose levels, lipid panel, and erythrocyte sedimentation rate. Serum protein electrophoresis was normal and no Bence Jones proteins were detected. Serum IgA, IgG, and IgM levels showed no abnormalities. Electrocardiogram, chest radiography, and abdominal ultrasound were normal.

A diagnosis of primary localized cutaneous nodular amyloidosis (PLCNA) was made based on clinical, histopathologic, and laboratory findings. Although surgical excision in stages was proposed, the patient refused treatment because the lesions were asymptomatic. There was no obvious progression of the skin lesions and no abnormal systemic findings during 2.5 years’ follow-up.

Comment

Amyloidosis is a spectrum of diseases consisting of deposition of amyloid proteins in various tissues. Clinically, amyloidosis is divided into both primary and secondary forms of systemic amyloidosis, hemodialysis-associated amyloidosis, heredofamilial amyloidosis, and cutaneous amyloidosis. Primary cutaneous amyloidosis is localized to the skin without other organ involvement and does not occur in systemic amyloidosis. Secondary cutaneous involvement in systemic amyloidosis is rare. Most cases of primary localized cutaneous amyloidosis (PLCA) are sporadic but approximately 10% of cases may be familial.¹ There are 3 main forms of localized cutaneous amyloidosis: macular, lichen, and nodular amyloidosis. Nodular cutaneous amyloidosis is the rarest form of PLCA.

Nodular amyloidosis was first described by Gottron in 1950.² Its cutaneous lesions may present as single or multiple nodules, occasionally with overlying atrophic plaques. The lesions consist of firm, smooth-surfaced, waxy or rubbery, pink to tan papules, plaques, or nodules measuring up to several centimeters. On some lesions, surface telangiectasia may be seen. Bullous-appearing and anetodermalike lesions have been reported.³ The acral region is the most common location, followed by the legs, head, trunk, arms, and genitalia, respectively.⁴ In some cases the lesions can spontaneously improve over time. In our patient, the lesions were composed of both multiple nodules and atrophic plaques, which is uncommon.

The pathogenesis of amyloid deposition is still unknown. Cutaneous macular and lichen amyloidosis may originate from degenerated keratinocyte intermediate filaments. Nodular amyloidosis may represent a localized plasma cell dyscrasia that can be associated with a monoclonal gammopathy or multiple myeloma.⁵ Some components of amyloid in some cases of PLCNA may consist of κ and λ immunoglobulin light chains, with most reported cases being of the l subtype.⁶ The results of one study indicated that β₂-microglobulin was another major component of amyloid fibrils and that β₂-microglobulin was partly subjected to the modification of advanced glycation end product in PLCNA.⁷

The histopathologic examination of PLCNA is characterized by large deposits of amorphous, sometimes fissured, pale, eosinophilic material in the papillary dermis, reticular dermis, and subcutaneous fat. The overlying epidermis may exhibit flattened rete ridges. Amyloid may occur within vessel walls and adnexal structures, sometimes in a ring surrounding individual fat cells. Clinically, the lesions of PLCNA may be indistinguishable from nodular deposits of amyloid occurring in primary systemic amyloidosis or myeloma-associated amyloidosis. Histopathologically, PLCNA usually has a variable infiltrate of plasma cells and lymphocytes at the periphery or within the amyloid deposits,⁶ but no single stain is highly sensitive and specific. Congo red–stained deposits showed salmon pink amorphous material or apple green birefringence with polarizing microscopy.⁸ Amyloid derived from immunoglobulin light chains, including cutaneous nodular amyloid, also stain positive for anti-human λ light chain antibody on immunohistochemistry. Additionally, amyloid can stain positively with methyl violet and crystal violet Gram stains, Picrosirius red, thioflavin T, Dylon, and periodic acid–Schiff stains.

Clinically, some PLCNA lesions can be removed via surgical excision or laser if they are cosmetically disfiguring or symptomatic. Other methods have been attempted to improve the appearance of the lesions, such as intralesional corticosteroids, cryotherapy, and dermabrasion,⁹ but they usually are not helpful and have a high rate of recurrence. Although PLCNA often is a benign cutaneous disorder and some cases of PLCNA could be reactive diseases rather than neoplastic ones, some patients may develop underlying systemic amyloidosis or even paraproteinemia.¹⁰ Northcutt and Vanover¹¹ indicated that systemic amyloidosis may be expected in less than 15% of 47 patients with localized cutaneous amyloidosis during follow-up by reviewing most of the related literature. Some cases may be associated with Sjögren syndrome (SJS), CREST (calcinosis, Raynaud phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia) syndrome, dermatomyositis, and diabetes mellitus.^12-14 Polyclonal immunoglobulin amyloid has been reported only in PLCNA with SJS, which may be due to the fact that a certain population of SJS develops polyclonal B-cell proliferation and hyperglobulinemia.¹² Woollons and Black¹⁵ estimated the rate of progression of PLCNA to systemic amyloidosis to be only 7%, which is much lower than the rate in the literature by a large clinical follow-up study on PLCNA.¹⁶ However, all patients with PLCNA should have a systemic evaluation and should be advised to undergo long-term clinical follow-up to help prevent progression to systemic amyloidosis or plasma cell dyscrasia.

Case Report

Clinical Findings

A 65-year-old woman presented with multiple asymptomatic discrete nodules and atrophic plaques on the thighs of 4 years’ duration. The lesions had started as 2 small, asymptomatic, madder red plaques symmetrically located on the anterior aspect of each thigh that had gradually increased in number and size, particularly on the right thigh. Two years later, 2 new atrophic plaques appeared on the anterior aspect of each. The lesions developed slowly but never remitted and had been misdiagnosed as primary macular atrophy of skin by several outpatient clinics. The patient’s general health was good and her personal and family history was unremarkable.

Physical examination revealed multiple madder red plaques and nodules of various shapes and sizes (ie, 1–3 cm in diameter) on the anterior aspect of the right thigh. The lesions were slightly elevated with a waxy surface, firm, and painless to palpation. One similar lesion was noted on the anterior aspect of the left thigh. Two 2-cm, brown-red, atrophic plaques also were noted in a symmetrical distribution on the anterior aspect of each thigh. The plaque surfaces were slightly crinkly and shiny, and anetodermalike lesions produced a buttonhole sign identical to a neurofibroma on palpation (Figure 1).

Figure 1. Multiple madder red plaques, nodules, and atrophic plaques in various shapes and sizes were seen on the anterior aspect of both thighs.

Histopathologic Findings

Two biopsy specimens were taken from a nodule and an atrophic plaque on the right thigh. Microscopic examination revealed deposition of homogeneous eosinophilic material in the reticular dermis and subcutis as well as around the fine vessels (Figure 2A). There was mild cellular infiltration of lymphocytes, plasma cells, and giant cells in the dermis, especially adjacent to deposits and around the vessels (Figure 2B). The homogeneous material appeared salmon pink on Congo red staining and bright green by thioflavin T staining using a fluorescent microscope (Figures 3 and 4). These results suggested the characteristic features of cutaneous nodular amyloidosis.

Figure 2. Histopathologically, homogeneous eosinophilic material deposited in the reticular dermis and subcutis was noted (A)(H&E, original magnification ×25). Microscopic examination showed lymphocytes and plasma cells infiltrated in the dermis, especially adjacent to deposits and around the vessels (B)(H&E, original magnification ×200).

Figure 3. Congo red staining showed salmon pink homogeneous material (original magnification ×25).

Figure 4. Thioflavin T staining showed bright green homogeneous material (original magnification ×100).

Laboratory Findings

Laboratory studies showed normal results for complete blood cell count, urinalysis, liver and renal function tests, blood glucose levels, lipid panel, and erythrocyte sedimentation rate. Serum protein electrophoresis was normal and no Bence Jones proteins were detected. Serum IgA, IgG, and IgM levels showed no abnormalities. Electrocardiogram, chest radiography, and abdominal ultrasound were normal.

A diagnosis of primary localized cutaneous nodular amyloidosis (PLCNA) was made based on clinical, histopathologic, and laboratory findings. Although surgical excision in stages was proposed, the patient refused treatment because the lesions were asymptomatic. There was no obvious progression of the skin lesions and no abnormal systemic findings during 2.5 years’ follow-up.

Comment

Amyloidosis is a spectrum of diseases consisting of deposition of amyloid proteins in various tissues. Clinically, amyloidosis is divided into both primary and secondary forms of systemic amyloidosis, hemodialysis-associated amyloidosis, heredofamilial amyloidosis, and cutaneous amyloidosis. Primary cutaneous amyloidosis is localized to the skin without other organ involvement and does not occur in systemic amyloidosis. Secondary cutaneous involvement in systemic amyloidosis is rare. Most cases of primary localized cutaneous amyloidosis (PLCA) are sporadic but approximately 10% of cases may be familial.¹ There are 3 main forms of localized cutaneous amyloidosis: macular, lichen, and nodular amyloidosis. Nodular cutaneous amyloidosis is the rarest form of PLCA.

Nodular amyloidosis was first described by Gottron in 1950.² Its cutaneous lesions may present as single or multiple nodules, occasionally with overlying atrophic plaques. The lesions consist of firm, smooth-surfaced, waxy or rubbery, pink to tan papules, plaques, or nodules measuring up to several centimeters. On some lesions, surface telangiectasia may be seen. Bullous-appearing and anetodermalike lesions have been reported.³ The acral region is the most common location, followed by the legs, head, trunk, arms, and genitalia, respectively.⁴ In some cases the lesions can spontaneously improve over time. In our patient, the lesions were composed of both multiple nodules and atrophic plaques, which is uncommon.

The pathogenesis of amyloid deposition is still unknown. Cutaneous macular and lichen amyloidosis may originate from degenerated keratinocyte intermediate filaments. Nodular amyloidosis may represent a localized plasma cell dyscrasia that can be associated with a monoclonal gammopathy or multiple myeloma.⁵ Some components of amyloid in some cases of PLCNA may consist of κ and λ immunoglobulin light chains, with most reported cases being of the l subtype.⁶ The results of one study indicated that β₂-microglobulin was another major component of amyloid fibrils and that β₂-microglobulin was partly subjected to the modification of advanced glycation end product in PLCNA.⁷

The histopathologic examination of PLCNA is characterized by large deposits of amorphous, sometimes fissured, pale, eosinophilic material in the papillary dermis, reticular dermis, and subcutaneous fat. The overlying epidermis may exhibit flattened rete ridges. Amyloid may occur within vessel walls and adnexal structures, sometimes in a ring surrounding individual fat cells. Clinically, the lesions of PLCNA may be indistinguishable from nodular deposits of amyloid occurring in primary systemic amyloidosis or myeloma-associated amyloidosis. Histopathologically, PLCNA usually has a variable infiltrate of plasma cells and lymphocytes at the periphery or within the amyloid deposits,⁶ but no single stain is highly sensitive and specific. Congo red–stained deposits showed salmon pink amorphous material or apple green birefringence with polarizing microscopy.⁸ Amyloid derived from immunoglobulin light chains, including cutaneous nodular amyloid, also stain positive for anti-human λ light chain antibody on immunohistochemistry. Additionally, amyloid can stain positively with methyl violet and crystal violet Gram stains, Picrosirius red, thioflavin T, Dylon, and periodic acid–Schiff stains.

Clinically, some PLCNA lesions can be removed via surgical excision or laser if they are cosmetically disfiguring or symptomatic. Other methods have been attempted to improve the appearance of the lesions, such as intralesional corticosteroids, cryotherapy, and dermabrasion,⁹ but they usually are not helpful and have a high rate of recurrence. Although PLCNA often is a benign cutaneous disorder and some cases of PLCNA could be reactive diseases rather than neoplastic ones, some patients may develop underlying systemic amyloidosis or even paraproteinemia.¹⁰ Northcutt and Vanover¹¹ indicated that systemic amyloidosis may be expected in less than 15% of 47 patients with localized cutaneous amyloidosis during follow-up by reviewing most of the related literature. Some cases may be associated with Sjögren syndrome (SJS), CREST (calcinosis, Raynaud phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia) syndrome, dermatomyositis, and diabetes mellitus.^12-14 Polyclonal immunoglobulin amyloid has been reported only in PLCNA with SJS, which may be due to the fact that a certain population of SJS develops polyclonal B-cell proliferation and hyperglobulinemia.¹² Woollons and Black¹⁵ estimated the rate of progression of PLCNA to systemic amyloidosis to be only 7%, which is much lower than the rate in the literature by a large clinical follow-up study on PLCNA.¹⁶ However, all patients with PLCNA should have a systemic evaluation and should be advised to undergo long-term clinical follow-up to help prevent progression to systemic amyloidosis or plasma cell dyscrasia.

Case Report

Clinical Findings

A 65-year-old woman presented with multiple asymptomatic discrete nodules and atrophic plaques on the thighs of 4 years’ duration. The lesions had started as 2 small, asymptomatic, madder red plaques symmetrically located on the anterior aspect of each thigh that had gradually increased in number and size, particularly on the right thigh. Two years later, 2 new atrophic plaques appeared on the anterior aspect of each. The lesions developed slowly but never remitted and had been misdiagnosed as primary macular atrophy of skin by several outpatient clinics. The patient’s general health was good and her personal and family history was unremarkable.

Physical examination revealed multiple madder red plaques and nodules of various shapes and sizes (ie, 1–3 cm in diameter) on the anterior aspect of the right thigh. The lesions were slightly elevated with a waxy surface, firm, and painless to palpation. One similar lesion was noted on the anterior aspect of the left thigh. Two 2-cm, brown-red, atrophic plaques also were noted in a symmetrical distribution on the anterior aspect of each thigh. The plaque surfaces were slightly crinkly and shiny, and anetodermalike lesions produced a buttonhole sign identical to a neurofibroma on palpation (Figure 1).

Figure 1. Multiple madder red plaques, nodules, and atrophic plaques in various shapes and sizes were seen on the anterior aspect of both thighs.

Histopathologic Findings

Two biopsy specimens were taken from a nodule and an atrophic plaque on the right thigh. Microscopic examination revealed deposition of homogeneous eosinophilic material in the reticular dermis and subcutis as well as around the fine vessels (Figure 2A). There was mild cellular infiltration of lymphocytes, plasma cells, and giant cells in the dermis, especially adjacent to deposits and around the vessels (Figure 2B). The homogeneous material appeared salmon pink on Congo red staining and bright green by thioflavin T staining using a fluorescent microscope (Figures 3 and 4). These results suggested the characteristic features of cutaneous nodular amyloidosis.

Figure 2. Histopathologically, homogeneous eosinophilic material deposited in the reticular dermis and subcutis was noted (A)(H&E, original magnification ×25). Microscopic examination showed lymphocytes and plasma cells infiltrated in the dermis, especially adjacent to deposits and around the vessels (B)(H&E, original magnification ×200).

Figure 3. Congo red staining showed salmon pink homogeneous material (original magnification ×25).

Figure 4. Thioflavin T staining showed bright green homogeneous material (original magnification ×100).

Laboratory Findings

Laboratory studies showed normal results for complete blood cell count, urinalysis, liver and renal function tests, blood glucose levels, lipid panel, and erythrocyte sedimentation rate. Serum protein electrophoresis was normal and no Bence Jones proteins were detected. Serum IgA, IgG, and IgM levels showed no abnormalities. Electrocardiogram, chest radiography, and abdominal ultrasound were normal.

A diagnosis of primary localized cutaneous nodular amyloidosis (PLCNA) was made based on clinical, histopathologic, and laboratory findings. Although surgical excision in stages was proposed, the patient refused treatment because the lesions were asymptomatic. There was no obvious progression of the skin lesions and no abnormal systemic findings during 2.5 years’ follow-up.

Comment

Amyloidosis is a spectrum of diseases consisting of deposition of amyloid proteins in various tissues. Clinically, amyloidosis is divided into both primary and secondary forms of systemic amyloidosis, hemodialysis-associated amyloidosis, heredofamilial amyloidosis, and cutaneous amyloidosis. Primary cutaneous amyloidosis is localized to the skin without other organ involvement and does not occur in systemic amyloidosis. Secondary cutaneous involvement in systemic amyloidosis is rare. Most cases of primary localized cutaneous amyloidosis (PLCA) are sporadic but approximately 10% of cases may be familial.¹ There are 3 main forms of localized cutaneous amyloidosis: macular, lichen, and nodular amyloidosis. Nodular cutaneous amyloidosis is the rarest form of PLCA.

Nodular amyloidosis was first described by Gottron in 1950.² Its cutaneous lesions may present as single or multiple nodules, occasionally with overlying atrophic plaques. The lesions consist of firm, smooth-surfaced, waxy or rubbery, pink to tan papules, plaques, or nodules measuring up to several centimeters. On some lesions, surface telangiectasia may be seen. Bullous-appearing and anetodermalike lesions have been reported.³ The acral region is the most common location, followed by the legs, head, trunk, arms, and genitalia, respectively.⁴ In some cases the lesions can spontaneously improve over time. In our patient, the lesions were composed of both multiple nodules and atrophic plaques, which is uncommon.

The pathogenesis of amyloid deposition is still unknown. Cutaneous macular and lichen amyloidosis may originate from degenerated keratinocyte intermediate filaments. Nodular amyloidosis may represent a localized plasma cell dyscrasia that can be associated with a monoclonal gammopathy or multiple myeloma.⁵ Some components of amyloid in some cases of PLCNA may consist of κ and λ immunoglobulin light chains, with most reported cases being of the l subtype.⁶ The results of one study indicated that β₂-microglobulin was another major component of amyloid fibrils and that β₂-microglobulin was partly subjected to the modification of advanced glycation end product in PLCNA.⁷

The histopathologic examination of PLCNA is characterized by large deposits of amorphous, sometimes fissured, pale, eosinophilic material in the papillary dermis, reticular dermis, and subcutaneous fat. The overlying epidermis may exhibit flattened rete ridges. Amyloid may occur within vessel walls and adnexal structures, sometimes in a ring surrounding individual fat cells. Clinically, the lesions of PLCNA may be indistinguishable from nodular deposits of amyloid occurring in primary systemic amyloidosis or myeloma-associated amyloidosis. Histopathologically, PLCNA usually has a variable infiltrate of plasma cells and lymphocytes at the periphery or within the amyloid deposits,⁶ but no single stain is highly sensitive and specific. Congo red–stained deposits showed salmon pink amorphous material or apple green birefringence with polarizing microscopy.⁸ Amyloid derived from immunoglobulin light chains, including cutaneous nodular amyloid, also stain positive for anti-human λ light chain antibody on immunohistochemistry. Additionally, amyloid can stain positively with methyl violet and crystal violet Gram stains, Picrosirius red, thioflavin T, Dylon, and periodic acid–Schiff stains.

Clinically, some PLCNA lesions can be removed via surgical excision or laser if they are cosmetically disfiguring or symptomatic. Other methods have been attempted to improve the appearance of the lesions, such as intralesional corticosteroids, cryotherapy, and dermabrasion,⁹ but they usually are not helpful and have a high rate of recurrence. Although PLCNA often is a benign cutaneous disorder and some cases of PLCNA could be reactive diseases rather than neoplastic ones, some patients may develop underlying systemic amyloidosis or even paraproteinemia.¹⁰ Northcutt and Vanover¹¹ indicated that systemic amyloidosis may be expected in less than 15% of 47 patients with localized cutaneous amyloidosis during follow-up by reviewing most of the related literature. Some cases may be associated with Sjögren syndrome (SJS), CREST (calcinosis, Raynaud phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia) syndrome, dermatomyositis, and diabetes mellitus.^12-14 Polyclonal immunoglobulin amyloid has been reported only in PLCNA with SJS, which may be due to the fact that a certain population of SJS develops polyclonal B-cell proliferation and hyperglobulinemia.¹² Woollons and Black¹⁵ estimated the rate of progression of PLCNA to systemic amyloidosis to be only 7%, which is much lower than the rate in the literature by a large clinical follow-up study on PLCNA.¹⁶ However, all patients with PLCNA should have a systemic evaluation and should be advised to undergo long-term clinical follow-up to help prevent progression to systemic amyloidosis or plasma cell dyscrasia.

To the Editor:

Benign cephalic histiocytosis (BCH) falls into the group of non–Langerhans cell histiocytosis (non-LCH), which is characterized by a benign course and tendency toward spontaneous remission. Apart from BCH, the main types of non-LCH include juvenile xanthogranuloma, generalized eruptive histiocytoma, and xanthoma disseminatum.¹

Benign cephalic histiocytosis is a rare form of cutaneous histiocytosis in young children. It presents as a papular eruption on the head and has not been associated with internal organ involvement.^2-4 It was described in 1971 by Gianotti et al⁵ and was named infantile histiocytosis with intracytoplasmic worm-like bodies because electron microscopy revealed histiocytes with large cytoplasmatic inclusions composed of wormlike membranous profiles and absence of Birbeck granules. In BCH, skin lesions are located on the head including the face and sometimes on the neck. Lesions occasionally may appear on the trunk, buttocks, and thighs. Mucous membranes are not involved. The onset of disease is typical in the first year of life; however, the disease may begin within the first 3 years of life. An eruption is characterized by small, 2- to 8-mm, discrete, asymptomatic, tan to red-brown macules and papules. The lesions may persist for several months or years and subsequently flatten, becoming hyperpigmented briefly. They often completely resolve with time. Most children are otherwise healthy and developmentally normal^6-9; however, diabetes insipidus has been reported in some children with BCH.¹⁰

Histologic examination of skin samples reveals the infiltrate of histiocytes, which closely approaches the epidermis, accompanied by scattered lymphocytes and a few eosinophils.^1,2,11 The histiocytes express a typical macrophage marker CD68, whereas immunostaining for Langerhans cell markers such as CD1a and S-100 is negative.^3,9,12,13

A 2.5-year-old boy was admitted to our dermatology department with suspected cutaneous mastocytosis (CM). Since the age of 13 months, he had developed small, 4- to 8-mm, dark pinkish macules and papules localized on the cheeks (Figure 1). Physical examination performed in our center revealed yellowish macules and flat papules limited to the cheeks. Darier sign was negative. The boy was otherwise healthy and developmentally normal. All laboratory tests were within reference range and his family history was uneventful.

Figure 1. Maculopapular eruption of benign cephalic histiocytosis on the cheeks (A and B).

Histopathologic examination of the skin sample revealed a normotypic epidermis and scattered subepidermal infiltrates in the upper dermis. The infiltrates were composed of predominating histiocytes and a few mast cells and eosinophils (Figure 2). The histiocytes were slightly pleomorphic and had abundant clear cytoplasm, vesicular nuclei, and prominent nucleoli. Mitoses were absent in these cells. The majority of cells within the infiltrate expressed CD68 and were CD1a^- and S-100^-. However, occasional CD1a⁺ cells were seen. Immunostaining for mast cell marker CD117 was negative. Cutaneous mastocytosis was excluded and non-LCH was recognized. Based on the typical location, morphology, and immunophenotype of skin lesions, BCH was diagnosed. At 24-month follow-up, spontaneous regression of skin lesions was observed.

Gianotti et al⁷ described BCH as a separate entity of the non-LCH group of disorders and established its diagnostic criteria: (1) onset of disease within the first 3 years of life; (2) location of skin lesions on the scalp and lack of lesions on the hands, feet, mucous membranes, and internal organ involvement; (3) spontaneous complete remission of symptoms; and (4) monomorphic infiltration of histiocytes that do not express S-100 and CD1a.

The macular and flat, papular, pink-yellow or orange lesions visible on the face of our patient are characteristic of BCH. Moreover, the cheeks are the most typical location of a BCH eruption, as noted in our patient.^6,7,12 The presence of histiocytic infiltrates composed of CD68⁺ cells strongly support the diagnosis.^3,4,9-13 In contrast to other reports, occasional CD1a⁺ cells of Langerhans phenotype were found in our case.^3,9,11,12 The proliferation of Langerhans cells in the skin and internal organs and presence of langerin are characteristic of Langerhans cell histiocytosis (LCH).^1,4,14 The presence of a few CD1a cells in cases with clinical features compatible with non-LCH may suggest that some of these cases may represent a papular self-healing variant of LCH or may indicate that there is an overlap among the histiocytic syndromes (eg, non-LCH and LCH). Furthermore, many of benign histiocytic lesions may evolve over the course of time into the others.^12,13 Differential diagnosis of BCH should include other benign forms of cutaneous histiocytosis, particularly the small nodular variant of juvenile xanthogranuloma and generalized eruptive histiocytoma (GEH). Juvenile xanthogranuloma pre-sents as disseminated, yellowish, nodular lesions and may be associated with ocular involvement, whereas GEH is characterized by rapid onset of the disease and disseminated nodular eruption.^1,4

Figure 2. Skin section showing the upper and mid dermis infiltrated with slightly pleomorphic epithelioid histiocytic cells with clear cytoplasm and vesicular nuclei. Few accompanying lymphocytes and eosinophils were visible (H&E, original magnifications ×200 and ×400).

A close histologic relationship and presence of overlapping symptoms observed among BCH, GEH, and juvenile xanthogranuloma indicate that these entities fall into a spectrum of the same disorder. However, the presence of a uniform infiltrate of large foamy histiocytes readily distinguishes xanthomas from BCH.⁴ In some unusual clinical presentations of CM or in cases of the nodular form of the condition, there is a need to distinguish between non-LCH and CM, as in our patient. Darier sign, consisting of urtication and erythema appearing after mechanical irritation of the skin lesion, is pathognomonic for CM. Nevertheless, Darier sign is not sufficient to confirm CM when it is not pronounced. Therefore, histologic examination with the use of immunostaining plays a key role in the differential diagnosis of these disorders in children.¹⁵ Treatment of BCH is not recommended because of spontaneous remission of the disease.^1-5

Benign cephalic histiocytosis is a rare clinical form of non-LCH. No systemic or mucosal involvement has been described. Lesions often are confused with plane warts, but a biopsy is definitive. Therapy is not effective but fortunately none is necessary.

To the Editor:

Benign cephalic histiocytosis (BCH) falls into the group of non–Langerhans cell histiocytosis (non-LCH), which is characterized by a benign course and tendency toward spontaneous remission. Apart from BCH, the main types of non-LCH include juvenile xanthogranuloma, generalized eruptive histiocytoma, and xanthoma disseminatum.¹

Benign cephalic histiocytosis is a rare form of cutaneous histiocytosis in young children. It presents as a papular eruption on the head and has not been associated with internal organ involvement.^2-4 It was described in 1971 by Gianotti et al⁵ and was named infantile histiocytosis with intracytoplasmic worm-like bodies because electron microscopy revealed histiocytes with large cytoplasmatic inclusions composed of wormlike membranous profiles and absence of Birbeck granules. In BCH, skin lesions are located on the head including the face and sometimes on the neck. Lesions occasionally may appear on the trunk, buttocks, and thighs. Mucous membranes are not involved. The onset of disease is typical in the first year of life; however, the disease may begin within the first 3 years of life. An eruption is characterized by small, 2- to 8-mm, discrete, asymptomatic, tan to red-brown macules and papules. The lesions may persist for several months or years and subsequently flatten, becoming hyperpigmented briefly. They often completely resolve with time. Most children are otherwise healthy and developmentally normal^6-9; however, diabetes insipidus has been reported in some children with BCH.¹⁰

Histologic examination of skin samples reveals the infiltrate of histiocytes, which closely approaches the epidermis, accompanied by scattered lymphocytes and a few eosinophils.^1,2,11 The histiocytes express a typical macrophage marker CD68, whereas immunostaining for Langerhans cell markers such as CD1a and S-100 is negative.^3,9,12,13

A 2.5-year-old boy was admitted to our dermatology department with suspected cutaneous mastocytosis (CM). Since the age of 13 months, he had developed small, 4- to 8-mm, dark pinkish macules and papules localized on the cheeks (Figure 1). Physical examination performed in our center revealed yellowish macules and flat papules limited to the cheeks. Darier sign was negative. The boy was otherwise healthy and developmentally normal. All laboratory tests were within reference range and his family history was uneventful.

Figure 1. Maculopapular eruption of benign cephalic histiocytosis on the cheeks (A and B).

Histopathologic examination of the skin sample revealed a normotypic epidermis and scattered subepidermal infiltrates in the upper dermis. The infiltrates were composed of predominating histiocytes and a few mast cells and eosinophils (Figure 2). The histiocytes were slightly pleomorphic and had abundant clear cytoplasm, vesicular nuclei, and prominent nucleoli. Mitoses were absent in these cells. The majority of cells within the infiltrate expressed CD68 and were CD1a^- and S-100^-. However, occasional CD1a⁺ cells were seen. Immunostaining for mast cell marker CD117 was negative. Cutaneous mastocytosis was excluded and non-LCH was recognized. Based on the typical location, morphology, and immunophenotype of skin lesions, BCH was diagnosed. At 24-month follow-up, spontaneous regression of skin lesions was observed.

Gianotti et al⁷ described BCH as a separate entity of the non-LCH group of disorders and established its diagnostic criteria: (1) onset of disease within the first 3 years of life; (2) location of skin lesions on the scalp and lack of lesions on the hands, feet, mucous membranes, and internal organ involvement; (3) spontaneous complete remission of symptoms; and (4) monomorphic infiltration of histiocytes that do not express S-100 and CD1a.

The macular and flat, papular, pink-yellow or orange lesions visible on the face of our patient are characteristic of BCH. Moreover, the cheeks are the most typical location of a BCH eruption, as noted in our patient.^6,7,12 The presence of histiocytic infiltrates composed of CD68⁺ cells strongly support the diagnosis.^3,4,9-13 In contrast to other reports, occasional CD1a⁺ cells of Langerhans phenotype were found in our case.^3,9,11,12 The proliferation of Langerhans cells in the skin and internal organs and presence of langerin are characteristic of Langerhans cell histiocytosis (LCH).^1,4,14 The presence of a few CD1a cells in cases with clinical features compatible with non-LCH may suggest that some of these cases may represent a papular self-healing variant of LCH or may indicate that there is an overlap among the histiocytic syndromes (eg, non-LCH and LCH). Furthermore, many of benign histiocytic lesions may evolve over the course of time into the others.^12,13 Differential diagnosis of BCH should include other benign forms of cutaneous histiocytosis, particularly the small nodular variant of juvenile xanthogranuloma and generalized eruptive histiocytoma (GEH). Juvenile xanthogranuloma pre-sents as disseminated, yellowish, nodular lesions and may be associated with ocular involvement, whereas GEH is characterized by rapid onset of the disease and disseminated nodular eruption.^1,4

Figure 2. Skin section showing the upper and mid dermis infiltrated with slightly pleomorphic epithelioid histiocytic cells with clear cytoplasm and vesicular nuclei. Few accompanying lymphocytes and eosinophils were visible (H&E, original magnifications ×200 and ×400).

A close histologic relationship and presence of overlapping symptoms observed among BCH, GEH, and juvenile xanthogranuloma indicate that these entities fall into a spectrum of the same disorder. However, the presence of a uniform infiltrate of large foamy histiocytes readily distinguishes xanthomas from BCH.⁴ In some unusual clinical presentations of CM or in cases of the nodular form of the condition, there is a need to distinguish between non-LCH and CM, as in our patient. Darier sign, consisting of urtication and erythema appearing after mechanical irritation of the skin lesion, is pathognomonic for CM. Nevertheless, Darier sign is not sufficient to confirm CM when it is not pronounced. Therefore, histologic examination with the use of immunostaining plays a key role in the differential diagnosis of these disorders in children.¹⁵ Treatment of BCH is not recommended because of spontaneous remission of the disease.^1-5

Benign cephalic histiocytosis is a rare clinical form of non-LCH. No systemic or mucosal involvement has been described. Lesions often are confused with plane warts, but a biopsy is definitive. Therapy is not effective but fortunately none is necessary.

To the Editor:

Benign cephalic histiocytosis (BCH) falls into the group of non–Langerhans cell histiocytosis (non-LCH), which is characterized by a benign course and tendency toward spontaneous remission. Apart from BCH, the main types of non-LCH include juvenile xanthogranuloma, generalized eruptive histiocytoma, and xanthoma disseminatum.¹

Benign cephalic histiocytosis is a rare form of cutaneous histiocytosis in young children. It presents as a papular eruption on the head and has not been associated with internal organ involvement.^2-4 It was described in 1971 by Gianotti et al⁵ and was named infantile histiocytosis with intracytoplasmic worm-like bodies because electron microscopy revealed histiocytes with large cytoplasmatic inclusions composed of wormlike membranous profiles and absence of Birbeck granules. In BCH, skin lesions are located on the head including the face and sometimes on the neck. Lesions occasionally may appear on the trunk, buttocks, and thighs. Mucous membranes are not involved. The onset of disease is typical in the first year of life; however, the disease may begin within the first 3 years of life. An eruption is characterized by small, 2- to 8-mm, discrete, asymptomatic, tan to red-brown macules and papules. The lesions may persist for several months or years and subsequently flatten, becoming hyperpigmented briefly. They often completely resolve with time. Most children are otherwise healthy and developmentally normal^6-9; however, diabetes insipidus has been reported in some children with BCH.¹⁰

Histologic examination of skin samples reveals the infiltrate of histiocytes, which closely approaches the epidermis, accompanied by scattered lymphocytes and a few eosinophils.^1,2,11 The histiocytes express a typical macrophage marker CD68, whereas immunostaining for Langerhans cell markers such as CD1a and S-100 is negative.^3,9,12,13

A 2.5-year-old boy was admitted to our dermatology department with suspected cutaneous mastocytosis (CM). Since the age of 13 months, he had developed small, 4- to 8-mm, dark pinkish macules and papules localized on the cheeks (Figure 1). Physical examination performed in our center revealed yellowish macules and flat papules limited to the cheeks. Darier sign was negative. The boy was otherwise healthy and developmentally normal. All laboratory tests were within reference range and his family history was uneventful.

Figure 1. Maculopapular eruption of benign cephalic histiocytosis on the cheeks (A and B).

Histopathologic examination of the skin sample revealed a normotypic epidermis and scattered subepidermal infiltrates in the upper dermis. The infiltrates were composed of predominating histiocytes and a few mast cells and eosinophils (Figure 2). The histiocytes were slightly pleomorphic and had abundant clear cytoplasm, vesicular nuclei, and prominent nucleoli. Mitoses were absent in these cells. The majority of cells within the infiltrate expressed CD68 and were CD1a^- and S-100^-. However, occasional CD1a⁺ cells were seen. Immunostaining for mast cell marker CD117 was negative. Cutaneous mastocytosis was excluded and non-LCH was recognized. Based on the typical location, morphology, and immunophenotype of skin lesions, BCH was diagnosed. At 24-month follow-up, spontaneous regression of skin lesions was observed.

Gianotti et al⁷ described BCH as a separate entity of the non-LCH group of disorders and established its diagnostic criteria: (1) onset of disease within the first 3 years of life; (2) location of skin lesions on the scalp and lack of lesions on the hands, feet, mucous membranes, and internal organ involvement; (3) spontaneous complete remission of symptoms; and (4) monomorphic infiltration of histiocytes that do not express S-100 and CD1a.

The macular and flat, papular, pink-yellow or orange lesions visible on the face of our patient are characteristic of BCH. Moreover, the cheeks are the most typical location of a BCH eruption, as noted in our patient.^6,7,12 The presence of histiocytic infiltrates composed of CD68⁺ cells strongly support the diagnosis.^3,4,9-13 In contrast to other reports, occasional CD1a⁺ cells of Langerhans phenotype were found in our case.^3,9,11,12 The proliferation of Langerhans cells in the skin and internal organs and presence of langerin are characteristic of Langerhans cell histiocytosis (LCH).^1,4,14 The presence of a few CD1a cells in cases with clinical features compatible with non-LCH may suggest that some of these cases may represent a papular self-healing variant of LCH or may indicate that there is an overlap among the histiocytic syndromes (eg, non-LCH and LCH). Furthermore, many of benign histiocytic lesions may evolve over the course of time into the others.^12,13 Differential diagnosis of BCH should include other benign forms of cutaneous histiocytosis, particularly the small nodular variant of juvenile xanthogranuloma and generalized eruptive histiocytoma (GEH). Juvenile xanthogranuloma pre-sents as disseminated, yellowish, nodular lesions and may be associated with ocular involvement, whereas GEH is characterized by rapid onset of the disease and disseminated nodular eruption.^1,4

Figure 2. Skin section showing the upper and mid dermis infiltrated with slightly pleomorphic epithelioid histiocytic cells with clear cytoplasm and vesicular nuclei. Few accompanying lymphocytes and eosinophils were visible (H&E, original magnifications ×200 and ×400).

A close histologic relationship and presence of overlapping symptoms observed among BCH, GEH, and juvenile xanthogranuloma indicate that these entities fall into a spectrum of the same disorder. However, the presence of a uniform infiltrate of large foamy histiocytes readily distinguishes xanthomas from BCH.⁴ In some unusual clinical presentations of CM or in cases of the nodular form of the condition, there is a need to distinguish between non-LCH and CM, as in our patient. Darier sign, consisting of urtication and erythema appearing after mechanical irritation of the skin lesion, is pathognomonic for CM. Nevertheless, Darier sign is not sufficient to confirm CM when it is not pronounced. Therefore, histologic examination with the use of immunostaining plays a key role in the differential diagnosis of these disorders in children.¹⁵ Treatment of BCH is not recommended because of spontaneous remission of the disease.^1-5

Benign cephalic histiocytosis is a rare clinical form of non-LCH. No systemic or mucosal involvement has been described. Lesions often are confused with plane warts, but a biopsy is definitive. Therapy is not effective but fortunately none is necessary.