Dermatopathology

The Diagnosis: Solitary Fibrous Tumor

Solitary fibrous tumors (SFTs), as first described by Klemperer and Rabin1 in 1931, are relatively uncommon mesenchymal neoplasms that occur primarily in the pleura. This lesion is now known to affect many other extrathoracic sites, such as the liver, kidney, adrenal glands, thyroid, central nervous system, and soft tissue, with rare examples originating from the skin.² Okamura et al³ reported the first known case of cutaneous SFT in 1997, with most of the literature limited to case reports. Erdag et al² described one of the largest case series of primary cutaneous SFTs. These lesions can occur across a wide age range but tend to primarily affect middle-aged adults. Solitary fibrous tumors have been known to have no sex predilection; however, Erdag et al² found a male predominance with a male to female ratio of 4 to 1. 

Histopathologically, a cutaneous SFT is known to appear as a well-circumscribed nodular spindle cell proliferation arranged in interlacing fascicles with an abundant hyalinized collagen stroma (quiz image). Alternating hypocellular and hypercellular areas can be seen. Supporting vasculature often is relatively prominent, represented by angulated and branching staghorn blood vessels (Figure 1).² A common histopathologic finding of SFTs is a patternless pattern, which suggests that the tumor can have a variety of morphologic appearances (eg, storiform, fascicular, neural, herringbone growth patterns), making histologic diagnosis difficult (quiz image).⁴ Therefore, immunohistochemistry plays a large role in the diagnosis of this tumor. The most important positive markers include CD34, CD99, B-cell lymphoma 2 (BCL-2), and signal transducer and activator of transcription 6 (STAT6).⁵ Nuclear STAT6 staining is an immunomarker for NGFI-A binding protein 2 (NAB2)-STAT6 gene fusion, which is specific for SFT.^5,6 Vivero et al⁷ also reported glutamate receptor, inotropic, AMPA 2 (GRIA2) as a useful immunostain in SFT, though it is also expressed in dermatofibrosarcoma protuberans (DFSP). In this case, the clinical and histopathologic findings best supported a diagnosis of SFT. Some consider hemangiopericytomas to be examples of SFTs; however, true hemangiopericytomas lack the thick hyalinized collagen and hypercellular areas seen in SFT.

A cellular dermatofibroma generally presents as a single round, reddish brown papule or nodule approximately 0.5 to 1 cm in diameter that is firm to palpation with a central depression or dimple created over the lesion from the lateral pressure. Cellular dermatofibromas mostly occur in middle-aged adults, with the most common locations on the legs and on the sides of the trunk. They are thought to arise after injuries to the skin. On histopathologic examination, cellular dermatofibromas typically exhibit a proliferation of fibrohistiocytic cells with collagen trapping, often at the periphery of the tumor (Figure 2). Although cellular dermatofibromas appear clinically different than SFTs, they often mimic SFTs histopathologically. Immunostaining also can be helpful in differentiating cellular dermatofibromas in which cells stain positive for factor XIIIa. CD34 staining is negative.

Dermatofibrosarcoma protuberans usually appears as one or multiple firm, red to violaceous nodules or plaques. They most often occur on the trunk in middle-aged adults. Histopathologically, DFSP presents with a dense, hypercellular, spindle cell proliferation that demonstrates a typical storiform pattern. The tumor generally infiltrates into the deep dermis and subcutaneous adipose layer with characteristic adipocyte entrapment (Figure 3). Positive CD34 and negative factor XIIIa staining helps to differentiate DFSP from a cellular dermatofibroma. Immunohistochemically, it is more difficult to distinguish DFSP from SFT, as both are CD34⁺ spindle cell neoplasms that also stain positive for CD99 and BCL-2.² GRIA2 positivity also is seen in both SFT and DFSP.⁷ However, differentiation can be made on morphologic grounds alone, as DFSP has ill-defined tumor borders with adnexal and fat entrapment and SFT tends to be more circumscribed with prominent arborizing hyalinized vessels.⁸

Spindle cell lipoma (SCL) is an asymptomatic subcutaneous tumor commonly located on the back, neck, and shoulders in older patients, typically men. It often presents as a solitary lesion, though multiple lesions may occur. It is a well-circumscribed tumor of mature adipose tissue with areas of spindle cell proliferation and ropey collagen bundles (Figure 4). In early lesions, the spindle cell areas are myxoid with the presence of many mast cells.⁹ The spindle cells stain positive for CD34. Although spindle cell lipoma would be included in both the clinical and histopathologic differential diagnosis for SFT, its histopathologic features often are enough to differentiate SCL, which is highlighted by the aforementioned features as well as a relatively low cellularity and lack of ectatic vessels.⁸ However, discerning tumor variants, such as low-fat pseudoangiomatous SCL and lipomatous or myxoid SFT, might prove more challenging.

Nodular fasciitis typically presents as a rapidly growing subcutaneous nodule that may be tender. It is a benign reactive process usually affecting the arms and trunk of young to middle-aged adults, though it commonly involves the head and neck region in children.¹⁰ The tumor histopathologically appears as a well-circumscribed subcutaneous or fascial nodule with an angulated appearance. Spindle-shaped and stellate fibroblasts are loosely arranged in an edematous myxomatous stroma with a feathered appearance (Figure 5). Extravasated erythrocytes often are present. With time, collagen bundles become thicker and hyalinized. Immunohistochemical studies demonstrate positivity for vimentin, calponin, muscle-specific actin, and smooth muscle actin. Desmin, CD34, cytokeratin, and S-100 typically are negative.^10-12 Therefore, CD34 staining is one of the main differentiating factors between nodular fasciitis and SFTs.

The Diagnosis: Solitary Fibrous Tumor

Solitary fibrous tumors (SFTs), as first described by Klemperer and Rabin1 in 1931, are relatively uncommon mesenchymal neoplasms that occur primarily in the pleura. This lesion is now known to affect many other extrathoracic sites, such as the liver, kidney, adrenal glands, thyroid, central nervous system, and soft tissue, with rare examples originating from the skin.² Okamura et al³ reported the first known case of cutaneous SFT in 1997, with most of the literature limited to case reports. Erdag et al² described one of the largest case series of primary cutaneous SFTs. These lesions can occur across a wide age range but tend to primarily affect middle-aged adults. Solitary fibrous tumors have been known to have no sex predilection; however, Erdag et al² found a male predominance with a male to female ratio of 4 to 1. 

Histopathologically, a cutaneous SFT is known to appear as a well-circumscribed nodular spindle cell proliferation arranged in interlacing fascicles with an abundant hyalinized collagen stroma (quiz image). Alternating hypocellular and hypercellular areas can be seen. Supporting vasculature often is relatively prominent, represented by angulated and branching staghorn blood vessels (Figure 1).² A common histopathologic finding of SFTs is a patternless pattern, which suggests that the tumor can have a variety of morphologic appearances (eg, storiform, fascicular, neural, herringbone growth patterns), making histologic diagnosis difficult (quiz image).⁴ Therefore, immunohistochemistry plays a large role in the diagnosis of this tumor. The most important positive markers include CD34, CD99, B-cell lymphoma 2 (BCL-2), and signal transducer and activator of transcription 6 (STAT6).⁵ Nuclear STAT6 staining is an immunomarker for NGFI-A binding protein 2 (NAB2)-STAT6 gene fusion, which is specific for SFT.^5,6 Vivero et al⁷ also reported glutamate receptor, inotropic, AMPA 2 (GRIA2) as a useful immunostain in SFT, though it is also expressed in dermatofibrosarcoma protuberans (DFSP). In this case, the clinical and histopathologic findings best supported a diagnosis of SFT. Some consider hemangiopericytomas to be examples of SFTs; however, true hemangiopericytomas lack the thick hyalinized collagen and hypercellular areas seen in SFT.

A cellular dermatofibroma generally presents as a single round, reddish brown papule or nodule approximately 0.5 to 1 cm in diameter that is firm to palpation with a central depression or dimple created over the lesion from the lateral pressure. Cellular dermatofibromas mostly occur in middle-aged adults, with the most common locations on the legs and on the sides of the trunk. They are thought to arise after injuries to the skin. On histopathologic examination, cellular dermatofibromas typically exhibit a proliferation of fibrohistiocytic cells with collagen trapping, often at the periphery of the tumor (Figure 2). Although cellular dermatofibromas appear clinically different than SFTs, they often mimic SFTs histopathologically. Immunostaining also can be helpful in differentiating cellular dermatofibromas in which cells stain positive for factor XIIIa. CD34 staining is negative.

Dermatofibrosarcoma protuberans usually appears as one or multiple firm, red to violaceous nodules or plaques. They most often occur on the trunk in middle-aged adults. Histopathologically, DFSP presents with a dense, hypercellular, spindle cell proliferation that demonstrates a typical storiform pattern. The tumor generally infiltrates into the deep dermis and subcutaneous adipose layer with characteristic adipocyte entrapment (Figure 3). Positive CD34 and negative factor XIIIa staining helps to differentiate DFSP from a cellular dermatofibroma. Immunohistochemically, it is more difficult to distinguish DFSP from SFT, as both are CD34⁺ spindle cell neoplasms that also stain positive for CD99 and BCL-2.² GRIA2 positivity also is seen in both SFT and DFSP.⁷ However, differentiation can be made on morphologic grounds alone, as DFSP has ill-defined tumor borders with adnexal and fat entrapment and SFT tends to be more circumscribed with prominent arborizing hyalinized vessels.⁸

Spindle cell lipoma (SCL) is an asymptomatic subcutaneous tumor commonly located on the back, neck, and shoulders in older patients, typically men. It often presents as a solitary lesion, though multiple lesions may occur. It is a well-circumscribed tumor of mature adipose tissue with areas of spindle cell proliferation and ropey collagen bundles (Figure 4). In early lesions, the spindle cell areas are myxoid with the presence of many mast cells.⁹ The spindle cells stain positive for CD34. Although spindle cell lipoma would be included in both the clinical and histopathologic differential diagnosis for SFT, its histopathologic features often are enough to differentiate SCL, which is highlighted by the aforementioned features as well as a relatively low cellularity and lack of ectatic vessels.⁸ However, discerning tumor variants, such as low-fat pseudoangiomatous SCL and lipomatous or myxoid SFT, might prove more challenging.

Nodular fasciitis typically presents as a rapidly growing subcutaneous nodule that may be tender. It is a benign reactive process usually affecting the arms and trunk of young to middle-aged adults, though it commonly involves the head and neck region in children.¹⁰ The tumor histopathologically appears as a well-circumscribed subcutaneous or fascial nodule with an angulated appearance. Spindle-shaped and stellate fibroblasts are loosely arranged in an edematous myxomatous stroma with a feathered appearance (Figure 5). Extravasated erythrocytes often are present. With time, collagen bundles become thicker and hyalinized. Immunohistochemical studies demonstrate positivity for vimentin, calponin, muscle-specific actin, and smooth muscle actin. Desmin, CD34, cytokeratin, and S-100 typically are negative.^10-12 Therefore, CD34 staining is one of the main differentiating factors between nodular fasciitis and SFTs.

The Diagnosis: Solitary Fibrous Tumor

Solitary fibrous tumors (SFTs), as first described by Klemperer and Rabin1 in 1931, are relatively uncommon mesenchymal neoplasms that occur primarily in the pleura. This lesion is now known to affect many other extrathoracic sites, such as the liver, kidney, adrenal glands, thyroid, central nervous system, and soft tissue, with rare examples originating from the skin.² Okamura et al³ reported the first known case of cutaneous SFT in 1997, with most of the literature limited to case reports. Erdag et al² described one of the largest case series of primary cutaneous SFTs. These lesions can occur across a wide age range but tend to primarily affect middle-aged adults. Solitary fibrous tumors have been known to have no sex predilection; however, Erdag et al² found a male predominance with a male to female ratio of 4 to 1. 

Histopathologically, a cutaneous SFT is known to appear as a well-circumscribed nodular spindle cell proliferation arranged in interlacing fascicles with an abundant hyalinized collagen stroma (quiz image). Alternating hypocellular and hypercellular areas can be seen. Supporting vasculature often is relatively prominent, represented by angulated and branching staghorn blood vessels (Figure 1).² A common histopathologic finding of SFTs is a patternless pattern, which suggests that the tumor can have a variety of morphologic appearances (eg, storiform, fascicular, neural, herringbone growth patterns), making histologic diagnosis difficult (quiz image).⁴ Therefore, immunohistochemistry plays a large role in the diagnosis of this tumor. The most important positive markers include CD34, CD99, B-cell lymphoma 2 (BCL-2), and signal transducer and activator of transcription 6 (STAT6).⁵ Nuclear STAT6 staining is an immunomarker for NGFI-A binding protein 2 (NAB2)-STAT6 gene fusion, which is specific for SFT.^5,6 Vivero et al⁷ also reported glutamate receptor, inotropic, AMPA 2 (GRIA2) as a useful immunostain in SFT, though it is also expressed in dermatofibrosarcoma protuberans (DFSP). In this case, the clinical and histopathologic findings best supported a diagnosis of SFT. Some consider hemangiopericytomas to be examples of SFTs; however, true hemangiopericytomas lack the thick hyalinized collagen and hypercellular areas seen in SFT.

A cellular dermatofibroma generally presents as a single round, reddish brown papule or nodule approximately 0.5 to 1 cm in diameter that is firm to palpation with a central depression or dimple created over the lesion from the lateral pressure. Cellular dermatofibromas mostly occur in middle-aged adults, with the most common locations on the legs and on the sides of the trunk. They are thought to arise after injuries to the skin. On histopathologic examination, cellular dermatofibromas typically exhibit a proliferation of fibrohistiocytic cells with collagen trapping, often at the periphery of the tumor (Figure 2). Although cellular dermatofibromas appear clinically different than SFTs, they often mimic SFTs histopathologically. Immunostaining also can be helpful in differentiating cellular dermatofibromas in which cells stain positive for factor XIIIa. CD34 staining is negative.

Dermatofibrosarcoma protuberans usually appears as one or multiple firm, red to violaceous nodules or plaques. They most often occur on the trunk in middle-aged adults. Histopathologically, DFSP presents with a dense, hypercellular, spindle cell proliferation that demonstrates a typical storiform pattern. The tumor generally infiltrates into the deep dermis and subcutaneous adipose layer with characteristic adipocyte entrapment (Figure 3). Positive CD34 and negative factor XIIIa staining helps to differentiate DFSP from a cellular dermatofibroma. Immunohistochemically, it is more difficult to distinguish DFSP from SFT, as both are CD34⁺ spindle cell neoplasms that also stain positive for CD99 and BCL-2.² GRIA2 positivity also is seen in both SFT and DFSP.⁷ However, differentiation can be made on morphologic grounds alone, as DFSP has ill-defined tumor borders with adnexal and fat entrapment and SFT tends to be more circumscribed with prominent arborizing hyalinized vessels.⁸

Spindle cell lipoma (SCL) is an asymptomatic subcutaneous tumor commonly located on the back, neck, and shoulders in older patients, typically men. It often presents as a solitary lesion, though multiple lesions may occur. It is a well-circumscribed tumor of mature adipose tissue with areas of spindle cell proliferation and ropey collagen bundles (Figure 4). In early lesions, the spindle cell areas are myxoid with the presence of many mast cells.⁹ The spindle cells stain positive for CD34. Although spindle cell lipoma would be included in both the clinical and histopathologic differential diagnosis for SFT, its histopathologic features often are enough to differentiate SCL, which is highlighted by the aforementioned features as well as a relatively low cellularity and lack of ectatic vessels.⁸ However, discerning tumor variants, such as low-fat pseudoangiomatous SCL and lipomatous or myxoid SFT, might prove more challenging.

Nodular fasciitis typically presents as a rapidly growing subcutaneous nodule that may be tender. It is a benign reactive process usually affecting the arms and trunk of young to middle-aged adults, though it commonly involves the head and neck region in children.¹⁰ The tumor histopathologically appears as a well-circumscribed subcutaneous or fascial nodule with an angulated appearance. Spindle-shaped and stellate fibroblasts are loosely arranged in an edematous myxomatous stroma with a feathered appearance (Figure 5). Extravasated erythrocytes often are present. With time, collagen bundles become thicker and hyalinized. Immunohistochemical studies demonstrate positivity for vimentin, calponin, muscle-specific actin, and smooth muscle actin. Desmin, CD34, cytokeratin, and S-100 typically are negative.^10-12 Therefore, CD34 staining is one of the main differentiating factors between nodular fasciitis and SFTs.

The Diagnosis: Lymphomatoid Papulosis

Histopathologic and immunohistochemical examination of the ulcer revealed a dense nodular and diffuse infiltrate in the papillary and reticular dermis comprised predominantly of atypical, CD30⁺, small T cells and large lymphoid cells admixed with neutrophils and eosinophils (Figures 1 and 2). Tissue cultures and infectious stains were negative. The complete blood cell count, metabolic panel, serum lactate dehydrogenase level, and peripheral blood flow cytometry were normal. Correlation of the lesions' self-healing nature with the histopathologic and immunohistochemical findings led to a diagnosis of lymphomatoid papulosis (LyP). In light of this diagnosis, a shave biopsy was obtained of one of the patient's poikilodermatous patches and was found to be consistent with poikilodermatous mycosis fungoides (MF).

At 4-month follow-up, the patient reported that she continued to develop crops of 1 to 3 LyP lesions each month. She continued to deny systemic concerns, and the poikilodermatous MF appeared unchanged. As part of a hematologic workup, a positron emission tomography-computed tomography scan revealed glucose-avid lymph nodes in the axillary, supraclavicular, abdominal, and inguinal regions. These findings raised concern for possible lymphomatous involvement of the patient's MF. Systemic therapy may be required pending further surveillance.

Lymphomatoid papulosis is a chronic papulonecrotic disease characterized clinically by recurrent crops of self-healing papules. Histopathologically, LyP features a perivascular infiltrate with atypical dermal T cells. Macaulay¹ first described LyP in 1968 in a 41-year-old woman with a several-year history of continuously self-resolving crops of necrotic papules, noting the paradox between the patient's benign clinical course and malignant-seeming histology featuring "an alarming infiltrate of anaplastic cells." Since this report, LyP has continued to spur debate regarding its malignant potential but is now recognized as an indolent cutaneous T-cell lymphoma with an excellent prognosis.²

There are several histopathologic subtypes of LyP, the most common of which are type A, resembling Hodgkin lymphoma; type B, resembling MF; type C, resembling primary cutaneous anaplastic large cell lymphoma (C-ALCL); and type D, resembling aggressive epidermotropic CD8⁺ cutaneous T-cell lymphoma.² 

The multifocal ulcers and eschars of LyP may appropriately raise suspicion for an infectious process, as in the present case. Numerous reports show that LyP may be initially misdiagnosed as an infection, such as cellulitis,³ furunculosis,⁴ parapoxvirus Orf,⁵ and ecthyma.⁶ Furthermore, several cutaneous infections have histopathologic features indistinguishable from LyP.⁷ For example, herpes simplex virus infection, molluscum contagiosum, Milker nodule, syphilis, and leishmaniasis may contain an appreciable number of large CD30⁺ T cells, which is compatible with both LyP type C and C-ALCL.⁷ As in the present case, the final diagnosis rests on clinicopathologic correlation, with LyP often distinguished by its invariable self-resolution, unlike its numerous infectious mimickers. The self-regressing nature of LyP also helps differentiate LyP occurring in the setting of MF from MF that has underwent CD30⁺ large cell transformation. In addition, the diagnosis of MF-associated LyP is favored over transformed MF when, as in the present case, CD30⁺ lesions develop on skin distinct from MF-affected skin.

Although isolated LyP is benign, 18% (11/61) of patients will subsequently develop lymphoma. More commonly, lymphomas may precede or occur concomitantly with the onset of LyP. In a retrospective study of 84 LyP patients, for example, 40% (34/84) had prior or concomitant lymphoma.8 Owing to the well-established link between LyP and lymphoma, there is appropriate emphasis on close monitoring of these patients. In addition, a careful history and physical examination are necessary to evaluate for a preceding, previously undiagnosed lymphoma. In point of fact, our patient had undiagnosed poikilodermatous MF prior to developing LyP, which was proven by biopsy at the time of LyP diagnosis. A distinct clinical variant of MF, poikilodermatous MF is characterized by hyperpigmented and hypopigmented patches, atrophy, and telangiectasia. A study of 49 patients with poikilodermatous MF found that this variant had an earlier age of onset compared with other types of MF. The study also showed that 18% (9/49) of patients had coexistent LyP, suggesting that poikilodermatous MF and LyP may be more frequently associated than previously believed.⁹

Treatment of LyP is unnecessary beyond basic wound care to avoid bacterial superinfection.^2,10 Therapy for poikilodermatous MF, similar to other types of MF, is based on disease stage. Topical therapy may be utilized for localized disease, while systemic therapies are reserved for recalcitrant cases and internal involvement.⁹
 
Acknowledgments
We thank David L. Ramsay, MD, for obtaining aspects of the patient's history, and Shane A. Meehan, MD, and Adnan Mir, MD, PhD, as well as Cynthia M. Magro, MD, (all from New York, New York) for performing the histopathologic and immunohistochemical analyses.

The Diagnosis: Lymphomatoid Papulosis

Histopathologic and immunohistochemical examination of the ulcer revealed a dense nodular and diffuse infiltrate in the papillary and reticular dermis comprised predominantly of atypical, CD30⁺, small T cells and large lymphoid cells admixed with neutrophils and eosinophils (Figures 1 and 2). Tissue cultures and infectious stains were negative. The complete blood cell count, metabolic panel, serum lactate dehydrogenase level, and peripheral blood flow cytometry were normal. Correlation of the lesions' self-healing nature with the histopathologic and immunohistochemical findings led to a diagnosis of lymphomatoid papulosis (LyP). In light of this diagnosis, a shave biopsy was obtained of one of the patient's poikilodermatous patches and was found to be consistent with poikilodermatous mycosis fungoides (MF).

At 4-month follow-up, the patient reported that she continued to develop crops of 1 to 3 LyP lesions each month. She continued to deny systemic concerns, and the poikilodermatous MF appeared unchanged. As part of a hematologic workup, a positron emission tomography-computed tomography scan revealed glucose-avid lymph nodes in the axillary, supraclavicular, abdominal, and inguinal regions. These findings raised concern for possible lymphomatous involvement of the patient's MF. Systemic therapy may be required pending further surveillance.

Lymphomatoid papulosis is a chronic papulonecrotic disease characterized clinically by recurrent crops of self-healing papules. Histopathologically, LyP features a perivascular infiltrate with atypical dermal T cells. Macaulay¹ first described LyP in 1968 in a 41-year-old woman with a several-year history of continuously self-resolving crops of necrotic papules, noting the paradox between the patient's benign clinical course and malignant-seeming histology featuring "an alarming infiltrate of anaplastic cells." Since this report, LyP has continued to spur debate regarding its malignant potential but is now recognized as an indolent cutaneous T-cell lymphoma with an excellent prognosis.²

There are several histopathologic subtypes of LyP, the most common of which are type A, resembling Hodgkin lymphoma; type B, resembling MF; type C, resembling primary cutaneous anaplastic large cell lymphoma (C-ALCL); and type D, resembling aggressive epidermotropic CD8⁺ cutaneous T-cell lymphoma.² 

The multifocal ulcers and eschars of LyP may appropriately raise suspicion for an infectious process, as in the present case. Numerous reports show that LyP may be initially misdiagnosed as an infection, such as cellulitis,³ furunculosis,⁴ parapoxvirus Orf,⁵ and ecthyma.⁶ Furthermore, several cutaneous infections have histopathologic features indistinguishable from LyP.⁷ For example, herpes simplex virus infection, molluscum contagiosum, Milker nodule, syphilis, and leishmaniasis may contain an appreciable number of large CD30⁺ T cells, which is compatible with both LyP type C and C-ALCL.⁷ As in the present case, the final diagnosis rests on clinicopathologic correlation, with LyP often distinguished by its invariable self-resolution, unlike its numerous infectious mimickers. The self-regressing nature of LyP also helps differentiate LyP occurring in the setting of MF from MF that has underwent CD30⁺ large cell transformation. In addition, the diagnosis of MF-associated LyP is favored over transformed MF when, as in the present case, CD30⁺ lesions develop on skin distinct from MF-affected skin.

Although isolated LyP is benign, 18% (11/61) of patients will subsequently develop lymphoma. More commonly, lymphomas may precede or occur concomitantly with the onset of LyP. In a retrospective study of 84 LyP patients, for example, 40% (34/84) had prior or concomitant lymphoma.8 Owing to the well-established link between LyP and lymphoma, there is appropriate emphasis on close monitoring of these patients. In addition, a careful history and physical examination are necessary to evaluate for a preceding, previously undiagnosed lymphoma. In point of fact, our patient had undiagnosed poikilodermatous MF prior to developing LyP, which was proven by biopsy at the time of LyP diagnosis. A distinct clinical variant of MF, poikilodermatous MF is characterized by hyperpigmented and hypopigmented patches, atrophy, and telangiectasia. A study of 49 patients with poikilodermatous MF found that this variant had an earlier age of onset compared with other types of MF. The study also showed that 18% (9/49) of patients had coexistent LyP, suggesting that poikilodermatous MF and LyP may be more frequently associated than previously believed.⁹

Treatment of LyP is unnecessary beyond basic wound care to avoid bacterial superinfection.^2,10 Therapy for poikilodermatous MF, similar to other types of MF, is based on disease stage. Topical therapy may be utilized for localized disease, while systemic therapies are reserved for recalcitrant cases and internal involvement.⁹
 
Acknowledgments
We thank David L. Ramsay, MD, for obtaining aspects of the patient's history, and Shane A. Meehan, MD, and Adnan Mir, MD, PhD, as well as Cynthia M. Magro, MD, (all from New York, New York) for performing the histopathologic and immunohistochemical analyses.

The Diagnosis: Lymphomatoid Papulosis

Histopathologic and immunohistochemical examination of the ulcer revealed a dense nodular and diffuse infiltrate in the papillary and reticular dermis comprised predominantly of atypical, CD30⁺, small T cells and large lymphoid cells admixed with neutrophils and eosinophils (Figures 1 and 2). Tissue cultures and infectious stains were negative. The complete blood cell count, metabolic panel, serum lactate dehydrogenase level, and peripheral blood flow cytometry were normal. Correlation of the lesions' self-healing nature with the histopathologic and immunohistochemical findings led to a diagnosis of lymphomatoid papulosis (LyP). In light of this diagnosis, a shave biopsy was obtained of one of the patient's poikilodermatous patches and was found to be consistent with poikilodermatous mycosis fungoides (MF).

At 4-month follow-up, the patient reported that she continued to develop crops of 1 to 3 LyP lesions each month. She continued to deny systemic concerns, and the poikilodermatous MF appeared unchanged. As part of a hematologic workup, a positron emission tomography-computed tomography scan revealed glucose-avid lymph nodes in the axillary, supraclavicular, abdominal, and inguinal regions. These findings raised concern for possible lymphomatous involvement of the patient's MF. Systemic therapy may be required pending further surveillance.

Lymphomatoid papulosis is a chronic papulonecrotic disease characterized clinically by recurrent crops of self-healing papules. Histopathologically, LyP features a perivascular infiltrate with atypical dermal T cells. Macaulay¹ first described LyP in 1968 in a 41-year-old woman with a several-year history of continuously self-resolving crops of necrotic papules, noting the paradox between the patient's benign clinical course and malignant-seeming histology featuring "an alarming infiltrate of anaplastic cells." Since this report, LyP has continued to spur debate regarding its malignant potential but is now recognized as an indolent cutaneous T-cell lymphoma with an excellent prognosis.²

There are several histopathologic subtypes of LyP, the most common of which are type A, resembling Hodgkin lymphoma; type B, resembling MF; type C, resembling primary cutaneous anaplastic large cell lymphoma (C-ALCL); and type D, resembling aggressive epidermotropic CD8⁺ cutaneous T-cell lymphoma.² 

The multifocal ulcers and eschars of LyP may appropriately raise suspicion for an infectious process, as in the present case. Numerous reports show that LyP may be initially misdiagnosed as an infection, such as cellulitis,³ furunculosis,⁴ parapoxvirus Orf,⁵ and ecthyma.⁶ Furthermore, several cutaneous infections have histopathologic features indistinguishable from LyP.⁷ For example, herpes simplex virus infection, molluscum contagiosum, Milker nodule, syphilis, and leishmaniasis may contain an appreciable number of large CD30⁺ T cells, which is compatible with both LyP type C and C-ALCL.⁷ As in the present case, the final diagnosis rests on clinicopathologic correlation, with LyP often distinguished by its invariable self-resolution, unlike its numerous infectious mimickers. The self-regressing nature of LyP also helps differentiate LyP occurring in the setting of MF from MF that has underwent CD30⁺ large cell transformation. In addition, the diagnosis of MF-associated LyP is favored over transformed MF when, as in the present case, CD30⁺ lesions develop on skin distinct from MF-affected skin.

Although isolated LyP is benign, 18% (11/61) of patients will subsequently develop lymphoma. More commonly, lymphomas may precede or occur concomitantly with the onset of LyP. In a retrospective study of 84 LyP patients, for example, 40% (34/84) had prior or concomitant lymphoma.8 Owing to the well-established link between LyP and lymphoma, there is appropriate emphasis on close monitoring of these patients. In addition, a careful history and physical examination are necessary to evaluate for a preceding, previously undiagnosed lymphoma. In point of fact, our patient had undiagnosed poikilodermatous MF prior to developing LyP, which was proven by biopsy at the time of LyP diagnosis. A distinct clinical variant of MF, poikilodermatous MF is characterized by hyperpigmented and hypopigmented patches, atrophy, and telangiectasia. A study of 49 patients with poikilodermatous MF found that this variant had an earlier age of onset compared with other types of MF. The study also showed that 18% (9/49) of patients had coexistent LyP, suggesting that poikilodermatous MF and LyP may be more frequently associated than previously believed.⁹

Treatment of LyP is unnecessary beyond basic wound care to avoid bacterial superinfection.^2,10 Therapy for poikilodermatous MF, similar to other types of MF, is based on disease stage. Topical therapy may be utilized for localized disease, while systemic therapies are reserved for recalcitrant cases and internal involvement.⁹
 
Acknowledgments
We thank David L. Ramsay, MD, for obtaining aspects of the patient's history, and Shane A. Meehan, MD, and Adnan Mir, MD, PhD, as well as Cynthia M. Magro, MD, (all from New York, New York) for performing the histopathologic and immunohistochemical analyses.

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.

The Diagnosis: Inverted Follicular Keratosis

The differential diagnosis for endophytic squamous neoplasms encompasses benign and malignant entities. The histologic findings of our patient's lesion were compatible with the diagnosis of inverted follicular keratosis (IFK), a benign neoplasm that usually presents as a keratotic papule on the head or neck. Histologically, IFK is characterized by an endophytic growth pattern with squamous eddies (quiz images). Inverted follicular keratosis may represent an irritated seborrheic keratosis or a distinct neoplasm derived from the infundibular portion of the hair follicle; the exact etiology is uncertain.^1,2 No relationship between IFK and human papillomavirus (HPV) has been established.³ Inverted follicular keratosis can mimic squamous cell carcinoma (SCC). Important clues to the diagnosis of IFK are the presence of squamous eddies and the lack of squamous pearls or cytologic atypia.⁴ Squamous eddies consist of whorled keratinocytes without keratinization or atypia. Superficial shave biopsies may fail to demonstrate the characteristic well-circumscribed architecture and may lead to an erroneous diagnosis.

Acantholytic SCC is characterized by atypical keratinocytes that have lost cohesive properties, resulting in acantholysis (Figure 1).⁵ This histologic variant was once categorized as an aggressive variant of SCC, but studies have failed to support this assertion.^5,6 Acantholytic SCC has a discohesive nature producing a pseudoglandular appearance sometimes mistaken for adenosquamous carcinoma or metastatic carcinoma. Recent literature has suggested that acantholytic SCCs, similar to IFKs, are derived from the follicular infundibulum.^5,6 Also similar to IFKs, acantholytic SCCs often are located on the face. The invasive architecture and atypical cytology of acantholytic SCCs can differentiate them from IFKs. Acantholytic SCCs can contain keratin pearls with concentric keratinocytes showing incomplete keratinization centrally, often with retained nuclei, but rare to no squamous eddies unless irritated.

Trichilemmoma is an endophytic benign neoplasm derived from the outer sheath of the pilosebaceous follicle characterized by lobules of clear cells hanging from the epidermis.⁷ A study investigating the relationship between HPV and trichilemmomas failed to definitively detect HPV in trichilemmomas and this relationship remains unclear.⁸ Desmoplastic trichilemmoma is a subtype histologically characterized by jagged islands of epithelial cells separated by dense pink stroma and encased in a glassy basement membrane (Figure 2). The presence of desmoplasia and a jagged growth pattern can mimic invasive SCC, but the absence of cytologic atypia and the surrounding basement membrane differs from SCC.^4,7 Trichilemmomas typically are solitary, but multiple lesions are associated with Cowden syndrome. Cowden syndrome is a rare autosomal-dominant condition characterized by the presence of benign hamartomas and a predisposition to the development of malignancies including breast, endometrial, and thyroid cancers.^9,10 There is no such association with desmoplastic trichilemmomas.¹¹

Pilar sheath acanthoma is a benign neoplasm that clinically presents as a solitary flesh-colored nodule with a central pore containing keratin.¹² Histologically, pilar sheath acanthoma is similar to a dilated pore of Winer with the addition of acanthotic epidermal projections (Figure 3).

Warty dyskeratoma (WD) is a benign endophytic neoplasm traditionally seen as a solitary lesion histologically similar to Darier disease. Warty dyskeratomas are known to occur both on the skin and oral mucosa.¹³ Histologically, WD is characterized as a cup-shaped lesion with numerous villi at the base of the lesion along with acantholysis and dyskeratosis (Figure 4). The dyskeratotic cells in WD consist of corps ronds, which are cells with abundant pink cytoplasm, and small nuclei along with grains, which are flattened basophilic cells. These dyskeratotic cells help differentiate WD from IFK. Although they are endophytic neoplasms, WDs are well circumscribed and should not be confused with SCC. Despite this entity's name and histologic similarity to verrucae, no relationship with HPV has been established.¹⁴

The Diagnosis: Inverted Follicular Keratosis

The differential diagnosis for endophytic squamous neoplasms encompasses benign and malignant entities. The histologic findings of our patient's lesion were compatible with the diagnosis of inverted follicular keratosis (IFK), a benign neoplasm that usually presents as a keratotic papule on the head or neck. Histologically, IFK is characterized by an endophytic growth pattern with squamous eddies (quiz images). Inverted follicular keratosis may represent an irritated seborrheic keratosis or a distinct neoplasm derived from the infundibular portion of the hair follicle; the exact etiology is uncertain.^1,2 No relationship between IFK and human papillomavirus (HPV) has been established.³ Inverted follicular keratosis can mimic squamous cell carcinoma (SCC). Important clues to the diagnosis of IFK are the presence of squamous eddies and the lack of squamous pearls or cytologic atypia.⁴ Squamous eddies consist of whorled keratinocytes without keratinization or atypia. Superficial shave biopsies may fail to demonstrate the characteristic well-circumscribed architecture and may lead to an erroneous diagnosis.

Acantholytic SCC is characterized by atypical keratinocytes that have lost cohesive properties, resulting in acantholysis (Figure 1).⁵ This histologic variant was once categorized as an aggressive variant of SCC, but studies have failed to support this assertion.^5,6 Acantholytic SCC has a discohesive nature producing a pseudoglandular appearance sometimes mistaken for adenosquamous carcinoma or metastatic carcinoma. Recent literature has suggested that acantholytic SCCs, similar to IFKs, are derived from the follicular infundibulum.^5,6 Also similar to IFKs, acantholytic SCCs often are located on the face. The invasive architecture and atypical cytology of acantholytic SCCs can differentiate them from IFKs. Acantholytic SCCs can contain keratin pearls with concentric keratinocytes showing incomplete keratinization centrally, often with retained nuclei, but rare to no squamous eddies unless irritated.

Trichilemmoma is an endophytic benign neoplasm derived from the outer sheath of the pilosebaceous follicle characterized by lobules of clear cells hanging from the epidermis.⁷ A study investigating the relationship between HPV and trichilemmomas failed to definitively detect HPV in trichilemmomas and this relationship remains unclear.⁸ Desmoplastic trichilemmoma is a subtype histologically characterized by jagged islands of epithelial cells separated by dense pink stroma and encased in a glassy basement membrane (Figure 2). The presence of desmoplasia and a jagged growth pattern can mimic invasive SCC, but the absence of cytologic atypia and the surrounding basement membrane differs from SCC.^4,7 Trichilemmomas typically are solitary, but multiple lesions are associated with Cowden syndrome. Cowden syndrome is a rare autosomal-dominant condition characterized by the presence of benign hamartomas and a predisposition to the development of malignancies including breast, endometrial, and thyroid cancers.^9,10 There is no such association with desmoplastic trichilemmomas.¹¹

Pilar sheath acanthoma is a benign neoplasm that clinically presents as a solitary flesh-colored nodule with a central pore containing keratin.¹² Histologically, pilar sheath acanthoma is similar to a dilated pore of Winer with the addition of acanthotic epidermal projections (Figure 3).

Warty dyskeratoma (WD) is a benign endophytic neoplasm traditionally seen as a solitary lesion histologically similar to Darier disease. Warty dyskeratomas are known to occur both on the skin and oral mucosa.¹³ Histologically, WD is characterized as a cup-shaped lesion with numerous villi at the base of the lesion along with acantholysis and dyskeratosis (Figure 4). The dyskeratotic cells in WD consist of corps ronds, which are cells with abundant pink cytoplasm, and small nuclei along with grains, which are flattened basophilic cells. These dyskeratotic cells help differentiate WD from IFK. Although they are endophytic neoplasms, WDs are well circumscribed and should not be confused with SCC. Despite this entity's name and histologic similarity to verrucae, no relationship with HPV has been established.¹⁴

The Diagnosis: Inverted Follicular Keratosis

The differential diagnosis for endophytic squamous neoplasms encompasses benign and malignant entities. The histologic findings of our patient's lesion were compatible with the diagnosis of inverted follicular keratosis (IFK), a benign neoplasm that usually presents as a keratotic papule on the head or neck. Histologically, IFK is characterized by an endophytic growth pattern with squamous eddies (quiz images). Inverted follicular keratosis may represent an irritated seborrheic keratosis or a distinct neoplasm derived from the infundibular portion of the hair follicle; the exact etiology is uncertain.^1,2 No relationship between IFK and human papillomavirus (HPV) has been established.³ Inverted follicular keratosis can mimic squamous cell carcinoma (SCC). Important clues to the diagnosis of IFK are the presence of squamous eddies and the lack of squamous pearls or cytologic atypia.⁴ Squamous eddies consist of whorled keratinocytes without keratinization or atypia. Superficial shave biopsies may fail to demonstrate the characteristic well-circumscribed architecture and may lead to an erroneous diagnosis.

Acantholytic SCC is characterized by atypical keratinocytes that have lost cohesive properties, resulting in acantholysis (Figure 1).⁵ This histologic variant was once categorized as an aggressive variant of SCC, but studies have failed to support this assertion.^5,6 Acantholytic SCC has a discohesive nature producing a pseudoglandular appearance sometimes mistaken for adenosquamous carcinoma or metastatic carcinoma. Recent literature has suggested that acantholytic SCCs, similar to IFKs, are derived from the follicular infundibulum.^5,6 Also similar to IFKs, acantholytic SCCs often are located on the face. The invasive architecture and atypical cytology of acantholytic SCCs can differentiate them from IFKs. Acantholytic SCCs can contain keratin pearls with concentric keratinocytes showing incomplete keratinization centrally, often with retained nuclei, but rare to no squamous eddies unless irritated.

Trichilemmoma is an endophytic benign neoplasm derived from the outer sheath of the pilosebaceous follicle characterized by lobules of clear cells hanging from the epidermis.⁷ A study investigating the relationship between HPV and trichilemmomas failed to definitively detect HPV in trichilemmomas and this relationship remains unclear.⁸ Desmoplastic trichilemmoma is a subtype histologically characterized by jagged islands of epithelial cells separated by dense pink stroma and encased in a glassy basement membrane (Figure 2). The presence of desmoplasia and a jagged growth pattern can mimic invasive SCC, but the absence of cytologic atypia and the surrounding basement membrane differs from SCC.^4,7 Trichilemmomas typically are solitary, but multiple lesions are associated with Cowden syndrome. Cowden syndrome is a rare autosomal-dominant condition characterized by the presence of benign hamartomas and a predisposition to the development of malignancies including breast, endometrial, and thyroid cancers.^9,10 There is no such association with desmoplastic trichilemmomas.¹¹

Pilar sheath acanthoma is a benign neoplasm that clinically presents as a solitary flesh-colored nodule with a central pore containing keratin.¹² Histologically, pilar sheath acanthoma is similar to a dilated pore of Winer with the addition of acanthotic epidermal projections (Figure 3).

Warty dyskeratoma (WD) is a benign endophytic neoplasm traditionally seen as a solitary lesion histologically similar to Darier disease. Warty dyskeratomas are known to occur both on the skin and oral mucosa.¹³ Histologically, WD is characterized as a cup-shaped lesion with numerous villi at the base of the lesion along with acantholysis and dyskeratosis (Figure 4). The dyskeratotic cells in WD consist of corps ronds, which are cells with abundant pink cytoplasm, and small nuclei along with grains, which are flattened basophilic cells. These dyskeratotic cells help differentiate WD from IFK. Although they are endophytic neoplasms, WDs are well circumscribed and should not be confused with SCC. Despite this entity's name and histologic similarity to verrucae, no relationship with HPV has been established.¹⁴

The Diagnosis: Antiphospholipid Antibody Syndrome

A  biopsy demonstrated scattered intravascular thrombi in the dermis and subcutis, intact vascular walls, and scant lymphocytic inflammation in a background of stasis (Figure 1). A periodic acid-Schiff stain was negative for fungal elements and highlighted the intravascular thrombi. Histologic findings were consistent with thrombotic vasculopathy. On further laboratory workup, lupus anticoagulant studies, including a mixing study, diluted Russell viper venom test, and hexagonal phase phospholipid neutralization test, were abnormal. Titers of anticardiolipin and β₂-glycoprotein I antibodies were elevated (anticardiolipin IgG, 137.7 calculated units [normal, <15 calculated units]; β₂-glycoprotein I IgG, 256.4 calculated units [normal, <20 calculated units]). Tissue cultures showed no growth of microorganisms and studies for cryoglobulinemia were negative.

The patient was diagnosed with primary antiphospholipid syndrome (APS). He remained on anticoagulation therapy with fondaparinux as an inpatient and was treated with pulse-dose intravenous (IV) corticosteroids followed by a slow oral taper, daily plasmapheresis for 1 week, IV immunoglobulin (0.5 g/kg) for 3 doses, and 4 weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks (Figure 2).

Antiphospholipid syndrome is an autoimmune disorder characterized by thrombotic events and the presence of autoantibodies. The syndrome is defined by 2 major criteria: (1) the occurrence of at least 1 clinical feature of either an episode of vascular thrombosis or pregnancy morbidity such as unexplained fetal death beyond 10 weeks of gestation or recurrent unexplained pregnancy losses; and (2) the presence of at least 1 type of autoantibody, including lupus anticoagulant, anticardiolipin, or β₂-glycoprotein antibodies, on 2 separate occasions at least 12 weeks apart.¹ Antiphospholipid syndrome can either be primary with no identifiable associated rheumatologic disease or secondary to another autoimmune disease such as systemic lupus erythematosus. Cutaneous manifestations are common and frequently are the first sign of disease in 30% to 40% of patients.² The most common skin finding is persistent livedo reticularis, which can be seen in 20% to 25% of patients. Patients also may develop skin necrosis, ulcerations, digital gangrene, splinter hemorrhages, and livedoid vasculopathy.² Systemic manifestations of APS include thrombocytopenia, nephropathy, cognitive dysfunction, and cardiac valve abnormalities. 

The exact pathogenesis of APS remains unknown. It is thought to be due to the combination of an inflammatory stimulus that has yet to be characterized in conjunction with autoantibodies that affect multiple target cells including monocytes, platelets, and endothelial cells, which results in activation of the complement system and clotting cascade.³ In rare cases, the disorder can progress to catastrophic antiphospholipid syndrome (CAPS), which requires fulfillment of 4 criteria: (1) evidence of involvement of 3 organs, tissues, or systems; (2) development of manifestations simultaneously or in less than 1 week; (3) laboratory confirmation of the presence of antiphospholipid antibodies; and (4) confirmation by histopathology of small vessel occlusion.⁴ Probable CAPS is diagnosed when 3 of 4 criteria are present. Our patient met criteria for probable CAPS, as his antibody titers remained elevated 15 weeks after initial presentation. Precipitating factors that can lead to CAPS are thought to include infection, surgical procedures, medications, or discontinuation of anticoagulation drugs.² Although the mainstay of management of APS is anticoagulation therapy with warfarin and antiplatelet agents such as aspirin, first-line treatment of CAPS involves high-dose systemic glucocorticoids and plasma exchange. Intravenous immunoglobulin also may be employed in treatment. Data from the CAPS registry demonstrate a role for rituximab, an anti-CD20 antibody, at 375 mg/m² weekly for 4 weeks (the regimen described in our case) or 1 g every 14 days for 2 sessions.⁵ A majority of the registry patients treated with rituximab recovered (75% [15/20]) and had no recurrent thrombosis (87% [13/15]) at follow-up.⁵ Data also are emerging on the role of eculizumab, an anti-C5 antibody that inhibits the terminal complement cascade, as a therapy in difficult-to-treat or refractory CAPS.^6-8 The prognosis for CAPS patients without treatment is poor, and mortality has been reported in up to 44% of patients. However, with intervention mortality is reduced by more than 2-fold.^9,10

It is important to recognize that acral cyanosis with persistent livedo reticularis and digital gangrene can be a presenting manifestation of APS. These cutaneous manifestations should prompt histologic evaluation for thrombotic vasculopathy in addition to serologic tests for APS autoantibodies. Although APS may be treated with anticoagulants and antiplatelet agents, CAPS may require more aggressive therapy with systemic steroids, plasma exchange, IV immunoglobulin, rituximab, and/or eculizumab.

The Diagnosis: Antiphospholipid Antibody Syndrome

A  biopsy demonstrated scattered intravascular thrombi in the dermis and subcutis, intact vascular walls, and scant lymphocytic inflammation in a background of stasis (Figure 1). A periodic acid-Schiff stain was negative for fungal elements and highlighted the intravascular thrombi. Histologic findings were consistent with thrombotic vasculopathy. On further laboratory workup, lupus anticoagulant studies, including a mixing study, diluted Russell viper venom test, and hexagonal phase phospholipid neutralization test, were abnormal. Titers of anticardiolipin and β₂-glycoprotein I antibodies were elevated (anticardiolipin IgG, 137.7 calculated units [normal, <15 calculated units]; β₂-glycoprotein I IgG, 256.4 calculated units [normal, <20 calculated units]). Tissue cultures showed no growth of microorganisms and studies for cryoglobulinemia were negative.

The patient was diagnosed with primary antiphospholipid syndrome (APS). He remained on anticoagulation therapy with fondaparinux as an inpatient and was treated with pulse-dose intravenous (IV) corticosteroids followed by a slow oral taper, daily plasmapheresis for 1 week, IV immunoglobulin (0.5 g/kg) for 3 doses, and 4 weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks (Figure 2).

Antiphospholipid syndrome is an autoimmune disorder characterized by thrombotic events and the presence of autoantibodies. The syndrome is defined by 2 major criteria: (1) the occurrence of at least 1 clinical feature of either an episode of vascular thrombosis or pregnancy morbidity such as unexplained fetal death beyond 10 weeks of gestation or recurrent unexplained pregnancy losses; and (2) the presence of at least 1 type of autoantibody, including lupus anticoagulant, anticardiolipin, or β₂-glycoprotein antibodies, on 2 separate occasions at least 12 weeks apart.¹ Antiphospholipid syndrome can either be primary with no identifiable associated rheumatologic disease or secondary to another autoimmune disease such as systemic lupus erythematosus. Cutaneous manifestations are common and frequently are the first sign of disease in 30% to 40% of patients.² The most common skin finding is persistent livedo reticularis, which can be seen in 20% to 25% of patients. Patients also may develop skin necrosis, ulcerations, digital gangrene, splinter hemorrhages, and livedoid vasculopathy.² Systemic manifestations of APS include thrombocytopenia, nephropathy, cognitive dysfunction, and cardiac valve abnormalities. 

The exact pathogenesis of APS remains unknown. It is thought to be due to the combination of an inflammatory stimulus that has yet to be characterized in conjunction with autoantibodies that affect multiple target cells including monocytes, platelets, and endothelial cells, which results in activation of the complement system and clotting cascade.³ In rare cases, the disorder can progress to catastrophic antiphospholipid syndrome (CAPS), which requires fulfillment of 4 criteria: (1) evidence of involvement of 3 organs, tissues, or systems; (2) development of manifestations simultaneously or in less than 1 week; (3) laboratory confirmation of the presence of antiphospholipid antibodies; and (4) confirmation by histopathology of small vessel occlusion.⁴ Probable CAPS is diagnosed when 3 of 4 criteria are present. Our patient met criteria for probable CAPS, as his antibody titers remained elevated 15 weeks after initial presentation. Precipitating factors that can lead to CAPS are thought to include infection, surgical procedures, medications, or discontinuation of anticoagulation drugs.² Although the mainstay of management of APS is anticoagulation therapy with warfarin and antiplatelet agents such as aspirin, first-line treatment of CAPS involves high-dose systemic glucocorticoids and plasma exchange. Intravenous immunoglobulin also may be employed in treatment. Data from the CAPS registry demonstrate a role for rituximab, an anti-CD20 antibody, at 375 mg/m² weekly for 4 weeks (the regimen described in our case) or 1 g every 14 days for 2 sessions.⁵ A majority of the registry patients treated with rituximab recovered (75% [15/20]) and had no recurrent thrombosis (87% [13/15]) at follow-up.⁵ Data also are emerging on the role of eculizumab, an anti-C5 antibody that inhibits the terminal complement cascade, as a therapy in difficult-to-treat or refractory CAPS.^6-8 The prognosis for CAPS patients without treatment is poor, and mortality has been reported in up to 44% of patients. However, with intervention mortality is reduced by more than 2-fold.^9,10

It is important to recognize that acral cyanosis with persistent livedo reticularis and digital gangrene can be a presenting manifestation of APS. These cutaneous manifestations should prompt histologic evaluation for thrombotic vasculopathy in addition to serologic tests for APS autoantibodies. Although APS may be treated with anticoagulants and antiplatelet agents, CAPS may require more aggressive therapy with systemic steroids, plasma exchange, IV immunoglobulin, rituximab, and/or eculizumab.

The Diagnosis: Antiphospholipid Antibody Syndrome

A  biopsy demonstrated scattered intravascular thrombi in the dermis and subcutis, intact vascular walls, and scant lymphocytic inflammation in a background of stasis (Figure 1). A periodic acid-Schiff stain was negative for fungal elements and highlighted the intravascular thrombi. Histologic findings were consistent with thrombotic vasculopathy. On further laboratory workup, lupus anticoagulant studies, including a mixing study, diluted Russell viper venom test, and hexagonal phase phospholipid neutralization test, were abnormal. Titers of anticardiolipin and β₂-glycoprotein I antibodies were elevated (anticardiolipin IgG, 137.7 calculated units [normal, <15 calculated units]; β₂-glycoprotein I IgG, 256.4 calculated units [normal, <20 calculated units]). Tissue cultures showed no growth of microorganisms and studies for cryoglobulinemia were negative.

The patient was diagnosed with primary antiphospholipid syndrome (APS). He remained on anticoagulation therapy with fondaparinux as an inpatient and was treated with pulse-dose intravenous (IV) corticosteroids followed by a slow oral taper, daily plasmapheresis for 1 week, IV immunoglobulin (0.5 g/kg) for 3 doses, and 4 weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks (Figure 2).

Antiphospholipid syndrome is an autoimmune disorder characterized by thrombotic events and the presence of autoantibodies. The syndrome is defined by 2 major criteria: (1) the occurrence of at least 1 clinical feature of either an episode of vascular thrombosis or pregnancy morbidity such as unexplained fetal death beyond 10 weeks of gestation or recurrent unexplained pregnancy losses; and (2) the presence of at least 1 type of autoantibody, including lupus anticoagulant, anticardiolipin, or β₂-glycoprotein antibodies, on 2 separate occasions at least 12 weeks apart.¹ Antiphospholipid syndrome can either be primary with no identifiable associated rheumatologic disease or secondary to another autoimmune disease such as systemic lupus erythematosus. Cutaneous manifestations are common and frequently are the first sign of disease in 30% to 40% of patients.² The most common skin finding is persistent livedo reticularis, which can be seen in 20% to 25% of patients. Patients also may develop skin necrosis, ulcerations, digital gangrene, splinter hemorrhages, and livedoid vasculopathy.² Systemic manifestations of APS include thrombocytopenia, nephropathy, cognitive dysfunction, and cardiac valve abnormalities. 

The exact pathogenesis of APS remains unknown. It is thought to be due to the combination of an inflammatory stimulus that has yet to be characterized in conjunction with autoantibodies that affect multiple target cells including monocytes, platelets, and endothelial cells, which results in activation of the complement system and clotting cascade.³ In rare cases, the disorder can progress to catastrophic antiphospholipid syndrome (CAPS), which requires fulfillment of 4 criteria: (1) evidence of involvement of 3 organs, tissues, or systems; (2) development of manifestations simultaneously or in less than 1 week; (3) laboratory confirmation of the presence of antiphospholipid antibodies; and (4) confirmation by histopathology of small vessel occlusion.⁴ Probable CAPS is diagnosed when 3 of 4 criteria are present. Our patient met criteria for probable CAPS, as his antibody titers remained elevated 15 weeks after initial presentation. Precipitating factors that can lead to CAPS are thought to include infection, surgical procedures, medications, or discontinuation of anticoagulation drugs.² Although the mainstay of management of APS is anticoagulation therapy with warfarin and antiplatelet agents such as aspirin, first-line treatment of CAPS involves high-dose systemic glucocorticoids and plasma exchange. Intravenous immunoglobulin also may be employed in treatment. Data from the CAPS registry demonstrate a role for rituximab, an anti-CD20 antibody, at 375 mg/m² weekly for 4 weeks (the regimen described in our case) or 1 g every 14 days for 2 sessions.⁵ A majority of the registry patients treated with rituximab recovered (75% [15/20]) and had no recurrent thrombosis (87% [13/15]) at follow-up.⁵ Data also are emerging on the role of eculizumab, an anti-C5 antibody that inhibits the terminal complement cascade, as a therapy in difficult-to-treat or refractory CAPS.^6-8 The prognosis for CAPS patients without treatment is poor, and mortality has been reported in up to 44% of patients. However, with intervention mortality is reduced by more than 2-fold.^9,10

It is important to recognize that acral cyanosis with persistent livedo reticularis and digital gangrene can be a presenting manifestation of APS. These cutaneous manifestations should prompt histologic evaluation for thrombotic vasculopathy in addition to serologic tests for APS autoantibodies. Although APS may be treated with anticoagulants and antiplatelet agents, CAPS may require more aggressive therapy with systemic steroids, plasma exchange, IV immunoglobulin, rituximab, and/or eculizumab.

In 1964, Sweet¹ described 8 women with acute onset of fever and erythematous plaques associated with a nonspecific infection of the respiratory or gastrointestinal tract. The lesions were histologically characterized by a neutrophilic infiltrate, and the author named the constellation of findings acute febrile neutrophilic dermatosis.¹ In 1968, Whittle et al² reported on similar cases and coined the term Sweet syndrome (SS).

Although the etiology and pathogenesis of SS remain unknown, several theories have been proposed. Because SS often is preceded by a respiratory or gastrointestinal tract infection, it has been postulated that it may represent a hypersensitivity reaction or may be related to local or systemic dysregulation of cytokine secretion.^3,4 In addition to respiratory or gastrointestinal tract infections, SS has been reported in association with malignancies, autoimmune diseases, drugs, vaccines, pregnancy, inflammatory bowel disease, and chemotherapy. It also may be idiopathic.⁵

The eruption of SS manifests as erythematous, indurated, and sharply demarcated plaques or nodules that typically favor the head, neck, and arms, with a particularly strong predilection for the dorsal aspects of the hands.⁶ Plaques and nodules are histologically characterized by a diffuse dermal neutrophilic infiltrate, papillary dermal edema, neutrophilic spongiosis, subcorneal pustules, and leukocytoclasia. Vasculitic features are not seen.⁷ The eruption typically resolves spontaneously in 5 to 12 weeks but recurs in approximately 30% of cases.⁸ Relatively common extracutaneous findings include ocular involvement, arthralgia, myalgia, and arthritis.^4,9 Both cutaneous and extracutaneous findings typically are responsive to prednisone at a dosage of 0.5 to 1 mg/kg daily for 4 to 6 weeks. Prolonged low-dose prednisone for 2 to 3 additional months may be necessary to suppress recurrence.⁸ Potassium iodide at 900 mg daily may be used as an alternative regimen.^3,8

Sweet syndrome is divided into 5 subcategories based on the underlying etiology: (1) classic or idiopathic, (2) paraneoplastic, (3) inflammatory and/or autoimmune disease related, (4) pregnancy related, and (5) drug induced.³ Although drug-induced SS comprises the minority of total cases (<5%), its reported incidence has been rising in recent years and has been associated with an escalating number of medications.¹⁰ We report a rare case of SS induced by administration of oral acetaminophen-codeine.

Case Report

A 32-year-old man with a history of diabetes mellitus underwent postoperative repair of a facial fracture. The patient was administered an oral acetaminophen-codeine suspension for postoperative pain control. One week later, he developed a painful eruption on the forehead and presented to the emergency department. He was prescribed acetaminophen-codeine 300/30-mg tablets every 6 hours in addition to hydrocortisone cream 1% applied every 6 hours. After this reintroduction of oral acetaminophen-codeine, he experienced intermittent fevers and an exacerbation of the initial cutaneous eruption. The patient presented for a second time 2 days after being seen in the emergency department and a dermatology consultation was obtained.

At the time of consultation, the patient was noted to have injected conjunctiva and erythematous, well-demarcated, and indurated plaques on the forehead with associated pain and burning (Figures 1A and 1B). Additional erythematous annular plaques were found on the palms, arms, and right knee. Laboratory workup revealed only mild anemia on complete blood cell count with a white blood cell count of 10.1×10⁹/L (reference range, 4.5–11.0×10⁹/L), hemoglobin of 12.9 g/dL (reference range, 14.0–17.4 g/dL), and hematocrit of 37.3% (reference range, 41%–50%). The platelet count was 284×10³/µL (reference range, 150–350×10³/µL). Basic metabolic panel was notable for an elevated glucose level of 418 mg/dL (reference range, 70–110 mg/dL). The most recent hemoglobin A_1C (several months prior) was notable at 14.7% of total hemoglobin (reference range, 4%–7% of total hemoglobin). A 4-mm punch biopsy of the right side of the forehead demonstrated minimal to mild papillary dermal edema and a diffuse dermal neutrophilic infiltrate spanning the upper, middle, and lower dermis with evidence of mild leukocytoclasia and no evidence of leukocytoclastic vasculitis (Figure 2). These histologic features together with the clinical presentation were consistent with a diagnosis of SS.

After an initial dose of intravenous methylprednisolone sodium succinate 125 mg in the emergency department, the patient was admitted for additional intravenous steroid administration in the context of uncontrolled hyperglycemia and history of poor glucose control. Upon admission, acetaminophen-codeine was discontinued and the patient was transitioned to intravenous methylprednisolone sodium succinate 60 mg every 8 hours. The patient also was given intravenous diphenhydramine 25 mg every 6 hours and desonide ointment 0.05% was applied to facial lesions. The inpatient medication regimen resulted in notable improvement of symptoms within 48 hours. Due to rapid improvement with steroids, no special stains for infectious etiologies were performed. The patient was discharged after 3 days in the hospital with triamcinolone ointment 0.1% to be applied to affected areas twice daily. The patient experienced no recurrence 2 months after treatment (Figure 1C).

 

Comment

Although SS itself is relatively rare, there has been an increasing incidence of the drug-induced subtype, most often in association with use of granulocyte colony-stimulating factor and granulocyte monocyte-stimulating factor. There also have been reported associations with a growing number of medications that include antibiotics, antiepileptic drugs, furosemide, hydralazine, and all-trans retinoic acid.^11-19 Moghimi et al¹¹ also reported an association with antivirals, cancer biotherapies, nonsteroidal anti-inflammatory drugs, psychotropes, azathioprine, oral contraceptives, and propylthiouracil.^10,20-26 Moghimi et al¹¹ further reported an association with several vaccines.

Several therapies for advanced melanoma also have been reviewed in the literature, including ipilimumab and vemurafenib,^27-30 as have several medications for the treatment of myelodysplastic syndrome including azacitidine.^31,32 A severe episode of drug-induced SS, predominantly on the legs, has been reported in association with lenalidomide, an immunomodulatory agent used in the treatment of myelodysplastic syndrome.³³

Additional medications more recently involved in the pathogenesis of drug-induced SS include the chemotherapeutic agents topetecan, mitoxantrone, gemcitabine, and vorinostat.^34-37 The antimalarial medication chloroquine also has been implicated, as have selective cyclooxygenase-2 inhibitors, hypomethylating agents, the tumor necrosis factor inhibitor adalimumab, IL-2 therapies, aripiprazole, and several other medications.^38-49

Despite drug-induced SS being reported in association with an increasing number of medications, there had been a lack of appropriate diagnostic criteria. To that end, Walker and Cohen⁵⁰ proposed 5 specific diagnostic criteria in 1996, including abrupt onset of painful erythematous plaques or nodules, histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, pyrexia (temperature >38°C), temporal relationship between drug ingestion and clinical presentation or temporally related recurrence after oral rechallenge, and temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.^50,51 Our patient met all of these criteria.

Conclusion

The number of cases of drug-induced SS in the literature continues to climb; however, the association with acetaminophen-codeine is unique. The importance of this case lies in educating both physicians and pharmacists alike regarding a newly recognized adverse effect of acetaminophen-codeine. Because acetaminophen-codeine often is used for its analgesic properties, and the predominant symptom of the cutaneous eruption of SS is pain, the therapeutic value of acetaminophen-codeine is substantially diminished in acetaminophen-codeine–induced SS. Accordingly, in these cases, the medication may be discontinued or substituted upon recognition of this adverse reaction to reduce patient morbidity.

In 1964, Sweet¹ described 8 women with acute onset of fever and erythematous plaques associated with a nonspecific infection of the respiratory or gastrointestinal tract. The lesions were histologically characterized by a neutrophilic infiltrate, and the author named the constellation of findings acute febrile neutrophilic dermatosis.¹ In 1968, Whittle et al² reported on similar cases and coined the term Sweet syndrome (SS).

Although the etiology and pathogenesis of SS remain unknown, several theories have been proposed. Because SS often is preceded by a respiratory or gastrointestinal tract infection, it has been postulated that it may represent a hypersensitivity reaction or may be related to local or systemic dysregulation of cytokine secretion.^3,4 In addition to respiratory or gastrointestinal tract infections, SS has been reported in association with malignancies, autoimmune diseases, drugs, vaccines, pregnancy, inflammatory bowel disease, and chemotherapy. It also may be idiopathic.⁵

The eruption of SS manifests as erythematous, indurated, and sharply demarcated plaques or nodules that typically favor the head, neck, and arms, with a particularly strong predilection for the dorsal aspects of the hands.⁶ Plaques and nodules are histologically characterized by a diffuse dermal neutrophilic infiltrate, papillary dermal edema, neutrophilic spongiosis, subcorneal pustules, and leukocytoclasia. Vasculitic features are not seen.⁷ The eruption typically resolves spontaneously in 5 to 12 weeks but recurs in approximately 30% of cases.⁸ Relatively common extracutaneous findings include ocular involvement, arthralgia, myalgia, and arthritis.^4,9 Both cutaneous and extracutaneous findings typically are responsive to prednisone at a dosage of 0.5 to 1 mg/kg daily for 4 to 6 weeks. Prolonged low-dose prednisone for 2 to 3 additional months may be necessary to suppress recurrence.⁸ Potassium iodide at 900 mg daily may be used as an alternative regimen.^3,8

Sweet syndrome is divided into 5 subcategories based on the underlying etiology: (1) classic or idiopathic, (2) paraneoplastic, (3) inflammatory and/or autoimmune disease related, (4) pregnancy related, and (5) drug induced.³ Although drug-induced SS comprises the minority of total cases (<5%), its reported incidence has been rising in recent years and has been associated with an escalating number of medications.¹⁰ We report a rare case of SS induced by administration of oral acetaminophen-codeine.

Case Report

A 32-year-old man with a history of diabetes mellitus underwent postoperative repair of a facial fracture. The patient was administered an oral acetaminophen-codeine suspension for postoperative pain control. One week later, he developed a painful eruption on the forehead and presented to the emergency department. He was prescribed acetaminophen-codeine 300/30-mg tablets every 6 hours in addition to hydrocortisone cream 1% applied every 6 hours. After this reintroduction of oral acetaminophen-codeine, he experienced intermittent fevers and an exacerbation of the initial cutaneous eruption. The patient presented for a second time 2 days after being seen in the emergency department and a dermatology consultation was obtained.

At the time of consultation, the patient was noted to have injected conjunctiva and erythematous, well-demarcated, and indurated plaques on the forehead with associated pain and burning (Figures 1A and 1B). Additional erythematous annular plaques were found on the palms, arms, and right knee. Laboratory workup revealed only mild anemia on complete blood cell count with a white blood cell count of 10.1×10⁹/L (reference range, 4.5–11.0×10⁹/L), hemoglobin of 12.9 g/dL (reference range, 14.0–17.4 g/dL), and hematocrit of 37.3% (reference range, 41%–50%). The platelet count was 284×10³/µL (reference range, 150–350×10³/µL). Basic metabolic panel was notable for an elevated glucose level of 418 mg/dL (reference range, 70–110 mg/dL). The most recent hemoglobin A_1C (several months prior) was notable at 14.7% of total hemoglobin (reference range, 4%–7% of total hemoglobin). A 4-mm punch biopsy of the right side of the forehead demonstrated minimal to mild papillary dermal edema and a diffuse dermal neutrophilic infiltrate spanning the upper, middle, and lower dermis with evidence of mild leukocytoclasia and no evidence of leukocytoclastic vasculitis (Figure 2). These histologic features together with the clinical presentation were consistent with a diagnosis of SS.

After an initial dose of intravenous methylprednisolone sodium succinate 125 mg in the emergency department, the patient was admitted for additional intravenous steroid administration in the context of uncontrolled hyperglycemia and history of poor glucose control. Upon admission, acetaminophen-codeine was discontinued and the patient was transitioned to intravenous methylprednisolone sodium succinate 60 mg every 8 hours. The patient also was given intravenous diphenhydramine 25 mg every 6 hours and desonide ointment 0.05% was applied to facial lesions. The inpatient medication regimen resulted in notable improvement of symptoms within 48 hours. Due to rapid improvement with steroids, no special stains for infectious etiologies were performed. The patient was discharged after 3 days in the hospital with triamcinolone ointment 0.1% to be applied to affected areas twice daily. The patient experienced no recurrence 2 months after treatment (Figure 1C).

 

Comment

Although SS itself is relatively rare, there has been an increasing incidence of the drug-induced subtype, most often in association with use of granulocyte colony-stimulating factor and granulocyte monocyte-stimulating factor. There also have been reported associations with a growing number of medications that include antibiotics, antiepileptic drugs, furosemide, hydralazine, and all-trans retinoic acid.^11-19 Moghimi et al¹¹ also reported an association with antivirals, cancer biotherapies, nonsteroidal anti-inflammatory drugs, psychotropes, azathioprine, oral contraceptives, and propylthiouracil.^10,20-26 Moghimi et al¹¹ further reported an association with several vaccines.

Several therapies for advanced melanoma also have been reviewed in the literature, including ipilimumab and vemurafenib,^27-30 as have several medications for the treatment of myelodysplastic syndrome including azacitidine.^31,32 A severe episode of drug-induced SS, predominantly on the legs, has been reported in association with lenalidomide, an immunomodulatory agent used in the treatment of myelodysplastic syndrome.³³

Additional medications more recently involved in the pathogenesis of drug-induced SS include the chemotherapeutic agents topetecan, mitoxantrone, gemcitabine, and vorinostat.^34-37 The antimalarial medication chloroquine also has been implicated, as have selective cyclooxygenase-2 inhibitors, hypomethylating agents, the tumor necrosis factor inhibitor adalimumab, IL-2 therapies, aripiprazole, and several other medications.^38-49

Despite drug-induced SS being reported in association with an increasing number of medications, there had been a lack of appropriate diagnostic criteria. To that end, Walker and Cohen⁵⁰ proposed 5 specific diagnostic criteria in 1996, including abrupt onset of painful erythematous plaques or nodules, histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, pyrexia (temperature >38°C), temporal relationship between drug ingestion and clinical presentation or temporally related recurrence after oral rechallenge, and temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.^50,51 Our patient met all of these criteria.

Conclusion

The number of cases of drug-induced SS in the literature continues to climb; however, the association with acetaminophen-codeine is unique. The importance of this case lies in educating both physicians and pharmacists alike regarding a newly recognized adverse effect of acetaminophen-codeine. Because acetaminophen-codeine often is used for its analgesic properties, and the predominant symptom of the cutaneous eruption of SS is pain, the therapeutic value of acetaminophen-codeine is substantially diminished in acetaminophen-codeine–induced SS. Accordingly, in these cases, the medication may be discontinued or substituted upon recognition of this adverse reaction to reduce patient morbidity.

In 1964, Sweet¹ described 8 women with acute onset of fever and erythematous plaques associated with a nonspecific infection of the respiratory or gastrointestinal tract. The lesions were histologically characterized by a neutrophilic infiltrate, and the author named the constellation of findings acute febrile neutrophilic dermatosis.¹ In 1968, Whittle et al² reported on similar cases and coined the term Sweet syndrome (SS).

Although the etiology and pathogenesis of SS remain unknown, several theories have been proposed. Because SS often is preceded by a respiratory or gastrointestinal tract infection, it has been postulated that it may represent a hypersensitivity reaction or may be related to local or systemic dysregulation of cytokine secretion.^3,4 In addition to respiratory or gastrointestinal tract infections, SS has been reported in association with malignancies, autoimmune diseases, drugs, vaccines, pregnancy, inflammatory bowel disease, and chemotherapy. It also may be idiopathic.⁵

The eruption of SS manifests as erythematous, indurated, and sharply demarcated plaques or nodules that typically favor the head, neck, and arms, with a particularly strong predilection for the dorsal aspects of the hands.⁶ Plaques and nodules are histologically characterized by a diffuse dermal neutrophilic infiltrate, papillary dermal edema, neutrophilic spongiosis, subcorneal pustules, and leukocytoclasia. Vasculitic features are not seen.⁷ The eruption typically resolves spontaneously in 5 to 12 weeks but recurs in approximately 30% of cases.⁸ Relatively common extracutaneous findings include ocular involvement, arthralgia, myalgia, and arthritis.^4,9 Both cutaneous and extracutaneous findings typically are responsive to prednisone at a dosage of 0.5 to 1 mg/kg daily for 4 to 6 weeks. Prolonged low-dose prednisone for 2 to 3 additional months may be necessary to suppress recurrence.⁸ Potassium iodide at 900 mg daily may be used as an alternative regimen.^3,8

Sweet syndrome is divided into 5 subcategories based on the underlying etiology: (1) classic or idiopathic, (2) paraneoplastic, (3) inflammatory and/or autoimmune disease related, (4) pregnancy related, and (5) drug induced.³ Although drug-induced SS comprises the minority of total cases (<5%), its reported incidence has been rising in recent years and has been associated with an escalating number of medications.¹⁰ We report a rare case of SS induced by administration of oral acetaminophen-codeine.

Case Report

A 32-year-old man with a history of diabetes mellitus underwent postoperative repair of a facial fracture. The patient was administered an oral acetaminophen-codeine suspension for postoperative pain control. One week later, he developed a painful eruption on the forehead and presented to the emergency department. He was prescribed acetaminophen-codeine 300/30-mg tablets every 6 hours in addition to hydrocortisone cream 1% applied every 6 hours. After this reintroduction of oral acetaminophen-codeine, he experienced intermittent fevers and an exacerbation of the initial cutaneous eruption. The patient presented for a second time 2 days after being seen in the emergency department and a dermatology consultation was obtained.

At the time of consultation, the patient was noted to have injected conjunctiva and erythematous, well-demarcated, and indurated plaques on the forehead with associated pain and burning (Figures 1A and 1B). Additional erythematous annular plaques were found on the palms, arms, and right knee. Laboratory workup revealed only mild anemia on complete blood cell count with a white blood cell count of 10.1×10⁹/L (reference range, 4.5–11.0×10⁹/L), hemoglobin of 12.9 g/dL (reference range, 14.0–17.4 g/dL), and hematocrit of 37.3% (reference range, 41%–50%). The platelet count was 284×10³/µL (reference range, 150–350×10³/µL). Basic metabolic panel was notable for an elevated glucose level of 418 mg/dL (reference range, 70–110 mg/dL). The most recent hemoglobin A_1C (several months prior) was notable at 14.7% of total hemoglobin (reference range, 4%–7% of total hemoglobin). A 4-mm punch biopsy of the right side of the forehead demonstrated minimal to mild papillary dermal edema and a diffuse dermal neutrophilic infiltrate spanning the upper, middle, and lower dermis with evidence of mild leukocytoclasia and no evidence of leukocytoclastic vasculitis (Figure 2). These histologic features together with the clinical presentation were consistent with a diagnosis of SS.

After an initial dose of intravenous methylprednisolone sodium succinate 125 mg in the emergency department, the patient was admitted for additional intravenous steroid administration in the context of uncontrolled hyperglycemia and history of poor glucose control. Upon admission, acetaminophen-codeine was discontinued and the patient was transitioned to intravenous methylprednisolone sodium succinate 60 mg every 8 hours. The patient also was given intravenous diphenhydramine 25 mg every 6 hours and desonide ointment 0.05% was applied to facial lesions. The inpatient medication regimen resulted in notable improvement of symptoms within 48 hours. Due to rapid improvement with steroids, no special stains for infectious etiologies were performed. The patient was discharged after 3 days in the hospital with triamcinolone ointment 0.1% to be applied to affected areas twice daily. The patient experienced no recurrence 2 months after treatment (Figure 1C).

 

Comment

Although SS itself is relatively rare, there has been an increasing incidence of the drug-induced subtype, most often in association with use of granulocyte colony-stimulating factor and granulocyte monocyte-stimulating factor. There also have been reported associations with a growing number of medications that include antibiotics, antiepileptic drugs, furosemide, hydralazine, and all-trans retinoic acid.^11-19 Moghimi et al¹¹ also reported an association with antivirals, cancer biotherapies, nonsteroidal anti-inflammatory drugs, psychotropes, azathioprine, oral contraceptives, and propylthiouracil.^10,20-26 Moghimi et al¹¹ further reported an association with several vaccines.

Several therapies for advanced melanoma also have been reviewed in the literature, including ipilimumab and vemurafenib,^27-30 as have several medications for the treatment of myelodysplastic syndrome including azacitidine.^31,32 A severe episode of drug-induced SS, predominantly on the legs, has been reported in association with lenalidomide, an immunomodulatory agent used in the treatment of myelodysplastic syndrome.³³

Additional medications more recently involved in the pathogenesis of drug-induced SS include the chemotherapeutic agents topetecan, mitoxantrone, gemcitabine, and vorinostat.^34-37 The antimalarial medication chloroquine also has been implicated, as have selective cyclooxygenase-2 inhibitors, hypomethylating agents, the tumor necrosis factor inhibitor adalimumab, IL-2 therapies, aripiprazole, and several other medications.^38-49

Despite drug-induced SS being reported in association with an increasing number of medications, there had been a lack of appropriate diagnostic criteria. To that end, Walker and Cohen⁵⁰ proposed 5 specific diagnostic criteria in 1996, including abrupt onset of painful erythematous plaques or nodules, histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, pyrexia (temperature >38°C), temporal relationship between drug ingestion and clinical presentation or temporally related recurrence after oral rechallenge, and temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.^50,51 Our patient met all of these criteria.

Conclusion

The number of cases of drug-induced SS in the literature continues to climb; however, the association with acetaminophen-codeine is unique. The importance of this case lies in educating both physicians and pharmacists alike regarding a newly recognized adverse effect of acetaminophen-codeine. Because acetaminophen-codeine often is used for its analgesic properties, and the predominant symptom of the cutaneous eruption of SS is pain, the therapeutic value of acetaminophen-codeine is substantially diminished in acetaminophen-codeine–induced SS. Accordingly, in these cases, the medication may be discontinued or substituted upon recognition of this adverse reaction to reduce patient morbidity.

Trichoblastomas are rare cutaneous tumors that recapitulate the germinative hair bulb and the surrounding mesenchyme. Although benign, they can present diagnostic difficulties for both the clinician and pathologist because of their rarity and overlap both clinically and microscopically with other follicular neoplasms as well as basal cell carcinoma (BCC). Several classification schemes for hair follicle neoplasms have been established based on the relative proportions of epithelial and mesenchymal components as well as stromal inductive change, but nomenclature continues to be problematic, as individual neoplasms show varying degrees of differentiation that do not always uniformly fit within these categories.^1,2 One of these established categories is a pigmented trichoblastoma.³ An exceedingly rare variant of a pigmented trichoblastoma referred to as melanotrichoblastoma was first described in 2002⁴ and has only been documented in 3 cases, according to a PubMed search of articles indexed for MEDLINE using the term melanotrichoblastoma.^4-6 We report another case of this rare tumor and review the literature on this unique group of tumors.

Case Report

A 25-year-old white woman with a medical history of chronic migraines, myofascial syndrome, and Arnold-Chiari malformation type I presented to dermatology with a 1.5-cm, pedunculated, well-circumscribed tumor on the left side of the scalp (Figure 1). The tumor was grossly flesh colored with heterogeneous areas of dark pigmentation. Microscopic examination demonstrated that within the superficial and deep dermis were variable-sized nests of basaloid cells. Some of the nests had large central cystic spaces with brown pigment within some of these spaces and focal pigmentation of the basaloid cells (Figure 2A). Focal areas of keratinization were present. Mitotic figures were easily identified; however, no atypical mitotic figures were present. Areas of peripheral palisading were present but there was no retraction artifact. Connection to the overlying epidermis was not identified. Surrounding the basaloid nodules was a mildly cellular proliferation of cytologically bland spindle cells. Occasional pigment-laden macrophages were present in the dermis. Focal areas suggestive of papillary mesenchymal body formation were present (Figure 2B). Immunohistochemical staining for Melan-A was performed and demonstrated the presence of a prominent number of melanocytes in some of the nests (Figure 3) and minimal to no melanocytes in other nests. There was no evidence of a melanocytic lesion involving the overlying epidermis. Features of nevus sebaceus were not present. Immunohistochemical staining for cytokeratin (CK) 20 was performed and demonstrated no notable number of Merkel cells within the lesion.

 

Comment

Overview of Trichoblastomas
Trichoblastomas most often present as solitary, flesh-colored, well-circumscribed, slow-growing tumors that usually progress in size over months to years. Although they may be present at any age, they most commonly occur in adults in the fifth to seventh decades of life and are equally distributed between males and females.^7,8 They most often occur on the head and neck with a predilection for the scalp. Although they behave in a benign fashion, cases of malignant trichoblastomas have been reported.⁹

Histopathology
Histologically, these tumors are well circumscribed but unencapsulated and usually located within the deep dermis, often with extension into the subcutaneous tissue. An epidermal connection is not identified. The tumor typically is composed of variable-sized nests of basaloid cells surrounded by a variable cellular stromal component. Although peripheral palisading is present in the basaloid component, retraction artifact is not present. Several histologic variants of trichoblastomas have been reported including cribriform, racemiform, retiform, pigmented, giant, subcutaneous, rippled pattern, and clear cell.⁵ Pigmented trichoblastomas are histologically similar to typical trichoblastomas, except for the presence of large amounts of melanin deposited within and around the tumor nests.⁶ A melanotrichoblastoma is a rare variant of a pigmented trichoblastoma; pigment is present in the lesion and melanocytes are identified within the basaloid nests.

The stromal component of trichoblastomas may show areas of condensation associated with some of the basaloid cells, resembling an attempt at hair bulb formation. Staining for CD10 will be positive in these areas of papillary mesenchymal bodies.¹⁰

In an immunohistochemical study of 13 cases of trichoblastomas, there was diffuse positive staining for CK14 and CK17 in all cases (similar to BCC) and positive staining for CK19 in 70% (9/13) of cases compared to 21% (4/19) of BCC cases. Staining for CK8 and CK20 demonstrated the presence of numerous Merkel cells in all trichoblastomas but in none of the 19 cases of BCC tested.¹¹ However, other studies have reported the presence of Merkel cells in only 42% to 70% of trichoblastomas.^12,13 Despite the lack of Merkel cells in our case, the lesion was interpreted as a melanotrichoblastoma based on the histologic features in conjunction with the presence of the melanocytes.

Differential Diagnosis
The clinical and histologic differential diagnosis of trichoblastomas includes both trichoepithelioma and BCC. Clinically, all 3 lesions often are slow growing, dome shaped, and small in size (several millimeters), and are observed in the same anatomic distribution of the head and neck region. Furthermore, they often affect middle-aged to older individuals and those of Caucasian descent, though other ethnicities can be affected. Histologic evaluation often is necessary to differentiate between these 3 entities.

Histologically, trichoepitheliomas are composed of nodules of basaloid cells encircled by stromal spindle cells. Although there can be histologic overlap between trichoepitheliomas and trichoblastoma, trichoepitheliomas typically will display obvious features of hair follicle differentiation with the presence of small keratinous cysts and hair bulb structures, while trichoblastomas tend to display minimal changes suggestive of its hair follicle origin. Similar to trichoblastomas, BCC is composed of nests of basaloid cells; however, BCCs often demonstrate retraction artifact and connection to the overlying epidermis. In addition, BCCs typically demonstrate a fibromucinous stromal component that is distinct from the cellular stroma of trichoblastic tumors. Immunoperoxidase staining for androgen receptors has been reported to be positive in 78% (25/32) of BCCs and negative in trichoblastic tumors.¹⁴

Melanotrichoblastoma Differentiating Characteristics
An exceedingly rare variant of pigmented trichoblastoma is the melanotrichoblastoma. There are clinical and histologic similarities and differences between the reported cases. The first case, described by Kanitakis et al,⁴ reported a 32-year-old black woman with a 2-cm scalp mass that slowly enlarged over the course of 2 years. The second case, presented by Kim et al,⁵ described a 51-year-old Korean man with a subcutaneous 6-cm mass on the back that had been present and slowly enlarging over the course of 5 years. The third case, reported by Hung et al,⁶ described a 34-year-old Taiwanese man with a 1-cm, left-sided, temporal scalp mass present for 3 years, arising from a nevus sebaceous. Comparing these clinical findings with our case of a 25-year-old white woman with a 1.5-cm mass on the left side of the scalp, melanotrichoblastomas demonstrate a relatively similar age of onset in the early to middle-aged adult years. All 4 tumors were slow growing. Additionally, 3 of 4 cases demonstrated a predilection for the head, particularly the scalp, and grossly showed well-circumscribed lesions with notable pigmentation. Although age, size, location, and gross appearance were similar, a comparable ethnic and gender demographic was not identified.

Microscopic similarities between the 4 cases were present. Each case was characterized by a large, well-circumscribed, unencapsulated, basaloid tumor present in the lower dermis, with only 1 case having tumor cells occasionally reaching the undersurface of the epidermis. The tumor cells were monomorphic round-ovoid in appearance with scant cytoplasm. There was melanin pigment in the basaloid nests. The basaloid nests were surrounded by a proliferation of stromal cells. The mitotic rate was sparse in 2 cases, brisk in 1 case, and not discussed in 1 case. Melanocytes were identified in the basaloid nests in all 4 cases; however, in the current case, the melanocytes were seen in only some of the nests. None of the cases exhibited an overlying junctional melanocytic lesion, which would argue against a possible collision tumor or colonization of an epithelial lesion by a melanocytic lesion.

Although the histologic features of our cases are consistent with prior reports of melanotrichoblastoma, there is some question as to whether it represents a true variant of a pigmented trichoblastoma. There are relatively few articles in the literature that describe pigmented trichoblastomas, and of those, immunohistochemistry staining for melanocytes is uncommon. In one of the earliest descriptions of a pigmented trichoblastoma, dendritic melanocytes were present within the tumor lobules; however, the lesion was reported as a pigmented trichoblastoma and not a melanotrichoblastoma.³ It is possible that all pigmented trichoblastomas may contain some number of dendritic melanocytes, thus negating the existence of a melanotrichoblastoma as a true subtype of pigmented trichoblastomas. Additional study looking at multiple examples of pigmented trichoblastomas would be required to more definitively classify melanotrichoblastomas. It is important to appreciate that at least some cases of pigmented trichoblastomas may contain melanocytes and not to confuse the lesion as representing an example of colonization or collision tumor. A rare case of melanoma possibly arising from these dendritic melanocytes has been reported.¹⁵

 

Conclusion

Trichoblastomas are uncommon tumors of germinative hair bulb origin that can have several histologic variants. A well-documented subtype of trichoblastoma characterized by melanin deposits within and around tumor nests has been identified and classified as a pigmented trichoblastoma. Four cases of melanotrichoblastoma have been reported and represent a variant of a pigmented trichoblastoma characterized by the presence of melanocytes within the lesion. Whether they represent a true variant is of some debate and additional study is required. Although these tumors are exceedingly rare, it is important for the clinician and pathologist to be aware of this entity to prevent confusion with other similarly appearing follicular lesions, most notably BCCs, because of the difference in treatment and follow-up.

Trichoblastomas are rare cutaneous tumors that recapitulate the germinative hair bulb and the surrounding mesenchyme. Although benign, they can present diagnostic difficulties for both the clinician and pathologist because of their rarity and overlap both clinically and microscopically with other follicular neoplasms as well as basal cell carcinoma (BCC). Several classification schemes for hair follicle neoplasms have been established based on the relative proportions of epithelial and mesenchymal components as well as stromal inductive change, but nomenclature continues to be problematic, as individual neoplasms show varying degrees of differentiation that do not always uniformly fit within these categories.^1,2 One of these established categories is a pigmented trichoblastoma.³ An exceedingly rare variant of a pigmented trichoblastoma referred to as melanotrichoblastoma was first described in 2002⁴ and has only been documented in 3 cases, according to a PubMed search of articles indexed for MEDLINE using the term melanotrichoblastoma.^4-6 We report another case of this rare tumor and review the literature on this unique group of tumors.

Case Report

A 25-year-old white woman with a medical history of chronic migraines, myofascial syndrome, and Arnold-Chiari malformation type I presented to dermatology with a 1.5-cm, pedunculated, well-circumscribed tumor on the left side of the scalp (Figure 1). The tumor was grossly flesh colored with heterogeneous areas of dark pigmentation. Microscopic examination demonstrated that within the superficial and deep dermis were variable-sized nests of basaloid cells. Some of the nests had large central cystic spaces with brown pigment within some of these spaces and focal pigmentation of the basaloid cells (Figure 2A). Focal areas of keratinization were present. Mitotic figures were easily identified; however, no atypical mitotic figures were present. Areas of peripheral palisading were present but there was no retraction artifact. Connection to the overlying epidermis was not identified. Surrounding the basaloid nodules was a mildly cellular proliferation of cytologically bland spindle cells. Occasional pigment-laden macrophages were present in the dermis. Focal areas suggestive of papillary mesenchymal body formation were present (Figure 2B). Immunohistochemical staining for Melan-A was performed and demonstrated the presence of a prominent number of melanocytes in some of the nests (Figure 3) and minimal to no melanocytes in other nests. There was no evidence of a melanocytic lesion involving the overlying epidermis. Features of nevus sebaceus were not present. Immunohistochemical staining for cytokeratin (CK) 20 was performed and demonstrated no notable number of Merkel cells within the lesion.

 

Comment

Overview of Trichoblastomas
Trichoblastomas most often present as solitary, flesh-colored, well-circumscribed, slow-growing tumors that usually progress in size over months to years. Although they may be present at any age, they most commonly occur in adults in the fifth to seventh decades of life and are equally distributed between males and females.^7,8 They most often occur on the head and neck with a predilection for the scalp. Although they behave in a benign fashion, cases of malignant trichoblastomas have been reported.⁹

Histopathology
Histologically, these tumors are well circumscribed but unencapsulated and usually located within the deep dermis, often with extension into the subcutaneous tissue. An epidermal connection is not identified. The tumor typically is composed of variable-sized nests of basaloid cells surrounded by a variable cellular stromal component. Although peripheral palisading is present in the basaloid component, retraction artifact is not present. Several histologic variants of trichoblastomas have been reported including cribriform, racemiform, retiform, pigmented, giant, subcutaneous, rippled pattern, and clear cell.⁵ Pigmented trichoblastomas are histologically similar to typical trichoblastomas, except for the presence of large amounts of melanin deposited within and around the tumor nests.⁶ A melanotrichoblastoma is a rare variant of a pigmented trichoblastoma; pigment is present in the lesion and melanocytes are identified within the basaloid nests.

The stromal component of trichoblastomas may show areas of condensation associated with some of the basaloid cells, resembling an attempt at hair bulb formation. Staining for CD10 will be positive in these areas of papillary mesenchymal bodies.¹⁰

In an immunohistochemical study of 13 cases of trichoblastomas, there was diffuse positive staining for CK14 and CK17 in all cases (similar to BCC) and positive staining for CK19 in 70% (9/13) of cases compared to 21% (4/19) of BCC cases. Staining for CK8 and CK20 demonstrated the presence of numerous Merkel cells in all trichoblastomas but in none of the 19 cases of BCC tested.¹¹ However, other studies have reported the presence of Merkel cells in only 42% to 70% of trichoblastomas.^12,13 Despite the lack of Merkel cells in our case, the lesion was interpreted as a melanotrichoblastoma based on the histologic features in conjunction with the presence of the melanocytes.

Differential Diagnosis
The clinical and histologic differential diagnosis of trichoblastomas includes both trichoepithelioma and BCC. Clinically, all 3 lesions often are slow growing, dome shaped, and small in size (several millimeters), and are observed in the same anatomic distribution of the head and neck region. Furthermore, they often affect middle-aged to older individuals and those of Caucasian descent, though other ethnicities can be affected. Histologic evaluation often is necessary to differentiate between these 3 entities.

Histologically, trichoepitheliomas are composed of nodules of basaloid cells encircled by stromal spindle cells. Although there can be histologic overlap between trichoepitheliomas and trichoblastoma, trichoepitheliomas typically will display obvious features of hair follicle differentiation with the presence of small keratinous cysts and hair bulb structures, while trichoblastomas tend to display minimal changes suggestive of its hair follicle origin. Similar to trichoblastomas, BCC is composed of nests of basaloid cells; however, BCCs often demonstrate retraction artifact and connection to the overlying epidermis. In addition, BCCs typically demonstrate a fibromucinous stromal component that is distinct from the cellular stroma of trichoblastic tumors. Immunoperoxidase staining for androgen receptors has been reported to be positive in 78% (25/32) of BCCs and negative in trichoblastic tumors.¹⁴

Melanotrichoblastoma Differentiating Characteristics
An exceedingly rare variant of pigmented trichoblastoma is the melanotrichoblastoma. There are clinical and histologic similarities and differences between the reported cases. The first case, described by Kanitakis et al,⁴ reported a 32-year-old black woman with a 2-cm scalp mass that slowly enlarged over the course of 2 years. The second case, presented by Kim et al,⁵ described a 51-year-old Korean man with a subcutaneous 6-cm mass on the back that had been present and slowly enlarging over the course of 5 years. The third case, reported by Hung et al,⁶ described a 34-year-old Taiwanese man with a 1-cm, left-sided, temporal scalp mass present for 3 years, arising from a nevus sebaceous. Comparing these clinical findings with our case of a 25-year-old white woman with a 1.5-cm mass on the left side of the scalp, melanotrichoblastomas demonstrate a relatively similar age of onset in the early to middle-aged adult years. All 4 tumors were slow growing. Additionally, 3 of 4 cases demonstrated a predilection for the head, particularly the scalp, and grossly showed well-circumscribed lesions with notable pigmentation. Although age, size, location, and gross appearance were similar, a comparable ethnic and gender demographic was not identified.

Microscopic similarities between the 4 cases were present. Each case was characterized by a large, well-circumscribed, unencapsulated, basaloid tumor present in the lower dermis, with only 1 case having tumor cells occasionally reaching the undersurface of the epidermis. The tumor cells were monomorphic round-ovoid in appearance with scant cytoplasm. There was melanin pigment in the basaloid nests. The basaloid nests were surrounded by a proliferation of stromal cells. The mitotic rate was sparse in 2 cases, brisk in 1 case, and not discussed in 1 case. Melanocytes were identified in the basaloid nests in all 4 cases; however, in the current case, the melanocytes were seen in only some of the nests. None of the cases exhibited an overlying junctional melanocytic lesion, which would argue against a possible collision tumor or colonization of an epithelial lesion by a melanocytic lesion.

Although the histologic features of our cases are consistent with prior reports of melanotrichoblastoma, there is some question as to whether it represents a true variant of a pigmented trichoblastoma. There are relatively few articles in the literature that describe pigmented trichoblastomas, and of those, immunohistochemistry staining for melanocytes is uncommon. In one of the earliest descriptions of a pigmented trichoblastoma, dendritic melanocytes were present within the tumor lobules; however, the lesion was reported as a pigmented trichoblastoma and not a melanotrichoblastoma.³ It is possible that all pigmented trichoblastomas may contain some number of dendritic melanocytes, thus negating the existence of a melanotrichoblastoma as a true subtype of pigmented trichoblastomas. Additional study looking at multiple examples of pigmented trichoblastomas would be required to more definitively classify melanotrichoblastomas. It is important to appreciate that at least some cases of pigmented trichoblastomas may contain melanocytes and not to confuse the lesion as representing an example of colonization or collision tumor. A rare case of melanoma possibly arising from these dendritic melanocytes has been reported.¹⁵

 

Conclusion

Trichoblastomas are uncommon tumors of germinative hair bulb origin that can have several histologic variants. A well-documented subtype of trichoblastoma characterized by melanin deposits within and around tumor nests has been identified and classified as a pigmented trichoblastoma. Four cases of melanotrichoblastoma have been reported and represent a variant of a pigmented trichoblastoma characterized by the presence of melanocytes within the lesion. Whether they represent a true variant is of some debate and additional study is required. Although these tumors are exceedingly rare, it is important for the clinician and pathologist to be aware of this entity to prevent confusion with other similarly appearing follicular lesions, most notably BCCs, because of the difference in treatment and follow-up.

Trichoblastomas are rare cutaneous tumors that recapitulate the germinative hair bulb and the surrounding mesenchyme. Although benign, they can present diagnostic difficulties for both the clinician and pathologist because of their rarity and overlap both clinically and microscopically with other follicular neoplasms as well as basal cell carcinoma (BCC). Several classification schemes for hair follicle neoplasms have been established based on the relative proportions of epithelial and mesenchymal components as well as stromal inductive change, but nomenclature continues to be problematic, as individual neoplasms show varying degrees of differentiation that do not always uniformly fit within these categories.^1,2 One of these established categories is a pigmented trichoblastoma.³ An exceedingly rare variant of a pigmented trichoblastoma referred to as melanotrichoblastoma was first described in 2002⁴ and has only been documented in 3 cases, according to a PubMed search of articles indexed for MEDLINE using the term melanotrichoblastoma.^4-6 We report another case of this rare tumor and review the literature on this unique group of tumors.

Case Report

A 25-year-old white woman with a medical history of chronic migraines, myofascial syndrome, and Arnold-Chiari malformation type I presented to dermatology with a 1.5-cm, pedunculated, well-circumscribed tumor on the left side of the scalp (Figure 1). The tumor was grossly flesh colored with heterogeneous areas of dark pigmentation. Microscopic examination demonstrated that within the superficial and deep dermis were variable-sized nests of basaloid cells. Some of the nests had large central cystic spaces with brown pigment within some of these spaces and focal pigmentation of the basaloid cells (Figure 2A). Focal areas of keratinization were present. Mitotic figures were easily identified; however, no atypical mitotic figures were present. Areas of peripheral palisading were present but there was no retraction artifact. Connection to the overlying epidermis was not identified. Surrounding the basaloid nodules was a mildly cellular proliferation of cytologically bland spindle cells. Occasional pigment-laden macrophages were present in the dermis. Focal areas suggestive of papillary mesenchymal body formation were present (Figure 2B). Immunohistochemical staining for Melan-A was performed and demonstrated the presence of a prominent number of melanocytes in some of the nests (Figure 3) and minimal to no melanocytes in other nests. There was no evidence of a melanocytic lesion involving the overlying epidermis. Features of nevus sebaceus were not present. Immunohistochemical staining for cytokeratin (CK) 20 was performed and demonstrated no notable number of Merkel cells within the lesion.

 

Comment

Overview of Trichoblastomas
Trichoblastomas most often present as solitary, flesh-colored, well-circumscribed, slow-growing tumors that usually progress in size over months to years. Although they may be present at any age, they most commonly occur in adults in the fifth to seventh decades of life and are equally distributed between males and females.^7,8 They most often occur on the head and neck with a predilection for the scalp. Although they behave in a benign fashion, cases of malignant trichoblastomas have been reported.⁹

Histopathology
Histologically, these tumors are well circumscribed but unencapsulated and usually located within the deep dermis, often with extension into the subcutaneous tissue. An epidermal connection is not identified. The tumor typically is composed of variable-sized nests of basaloid cells surrounded by a variable cellular stromal component. Although peripheral palisading is present in the basaloid component, retraction artifact is not present. Several histologic variants of trichoblastomas have been reported including cribriform, racemiform, retiform, pigmented, giant, subcutaneous, rippled pattern, and clear cell.⁵ Pigmented trichoblastomas are histologically similar to typical trichoblastomas, except for the presence of large amounts of melanin deposited within and around the tumor nests.⁶ A melanotrichoblastoma is a rare variant of a pigmented trichoblastoma; pigment is present in the lesion and melanocytes are identified within the basaloid nests.

The stromal component of trichoblastomas may show areas of condensation associated with some of the basaloid cells, resembling an attempt at hair bulb formation. Staining for CD10 will be positive in these areas of papillary mesenchymal bodies.¹⁰

In an immunohistochemical study of 13 cases of trichoblastomas, there was diffuse positive staining for CK14 and CK17 in all cases (similar to BCC) and positive staining for CK19 in 70% (9/13) of cases compared to 21% (4/19) of BCC cases. Staining for CK8 and CK20 demonstrated the presence of numerous Merkel cells in all trichoblastomas but in none of the 19 cases of BCC tested.¹¹ However, other studies have reported the presence of Merkel cells in only 42% to 70% of trichoblastomas.^12,13 Despite the lack of Merkel cells in our case, the lesion was interpreted as a melanotrichoblastoma based on the histologic features in conjunction with the presence of the melanocytes.

Differential Diagnosis
The clinical and histologic differential diagnosis of trichoblastomas includes both trichoepithelioma and BCC. Clinically, all 3 lesions often are slow growing, dome shaped, and small in size (several millimeters), and are observed in the same anatomic distribution of the head and neck region. Furthermore, they often affect middle-aged to older individuals and those of Caucasian descent, though other ethnicities can be affected. Histologic evaluation often is necessary to differentiate between these 3 entities.

Histologically, trichoepitheliomas are composed of nodules of basaloid cells encircled by stromal spindle cells. Although there can be histologic overlap between trichoepitheliomas and trichoblastoma, trichoepitheliomas typically will display obvious features of hair follicle differentiation with the presence of small keratinous cysts and hair bulb structures, while trichoblastomas tend to display minimal changes suggestive of its hair follicle origin. Similar to trichoblastomas, BCC is composed of nests of basaloid cells; however, BCCs often demonstrate retraction artifact and connection to the overlying epidermis. In addition, BCCs typically demonstrate a fibromucinous stromal component that is distinct from the cellular stroma of trichoblastic tumors. Immunoperoxidase staining for androgen receptors has been reported to be positive in 78% (25/32) of BCCs and negative in trichoblastic tumors.¹⁴

Melanotrichoblastoma Differentiating Characteristics
An exceedingly rare variant of pigmented trichoblastoma is the melanotrichoblastoma. There are clinical and histologic similarities and differences between the reported cases. The first case, described by Kanitakis et al,⁴ reported a 32-year-old black woman with a 2-cm scalp mass that slowly enlarged over the course of 2 years. The second case, presented by Kim et al,⁵ described a 51-year-old Korean man with a subcutaneous 6-cm mass on the back that had been present and slowly enlarging over the course of 5 years. The third case, reported by Hung et al,⁶ described a 34-year-old Taiwanese man with a 1-cm, left-sided, temporal scalp mass present for 3 years, arising from a nevus sebaceous. Comparing these clinical findings with our case of a 25-year-old white woman with a 1.5-cm mass on the left side of the scalp, melanotrichoblastomas demonstrate a relatively similar age of onset in the early to middle-aged adult years. All 4 tumors were slow growing. Additionally, 3 of 4 cases demonstrated a predilection for the head, particularly the scalp, and grossly showed well-circumscribed lesions with notable pigmentation. Although age, size, location, and gross appearance were similar, a comparable ethnic and gender demographic was not identified.

Microscopic similarities between the 4 cases were present. Each case was characterized by a large, well-circumscribed, unencapsulated, basaloid tumor present in the lower dermis, with only 1 case having tumor cells occasionally reaching the undersurface of the epidermis. The tumor cells were monomorphic round-ovoid in appearance with scant cytoplasm. There was melanin pigment in the basaloid nests. The basaloid nests were surrounded by a proliferation of stromal cells. The mitotic rate was sparse in 2 cases, brisk in 1 case, and not discussed in 1 case. Melanocytes were identified in the basaloid nests in all 4 cases; however, in the current case, the melanocytes were seen in only some of the nests. None of the cases exhibited an overlying junctional melanocytic lesion, which would argue against a possible collision tumor or colonization of an epithelial lesion by a melanocytic lesion.

Although the histologic features of our cases are consistent with prior reports of melanotrichoblastoma, there is some question as to whether it represents a true variant of a pigmented trichoblastoma. There are relatively few articles in the literature that describe pigmented trichoblastomas, and of those, immunohistochemistry staining for melanocytes is uncommon. In one of the earliest descriptions of a pigmented trichoblastoma, dendritic melanocytes were present within the tumor lobules; however, the lesion was reported as a pigmented trichoblastoma and not a melanotrichoblastoma.³ It is possible that all pigmented trichoblastomas may contain some number of dendritic melanocytes, thus negating the existence of a melanotrichoblastoma as a true subtype of pigmented trichoblastomas. Additional study looking at multiple examples of pigmented trichoblastomas would be required to more definitively classify melanotrichoblastomas. It is important to appreciate that at least some cases of pigmented trichoblastomas may contain melanocytes and not to confuse the lesion as representing an example of colonization or collision tumor. A rare case of melanoma possibly arising from these dendritic melanocytes has been reported.¹⁵

 

Conclusion

Trichoblastomas are uncommon tumors of germinative hair bulb origin that can have several histologic variants. A well-documented subtype of trichoblastoma characterized by melanin deposits within and around tumor nests has been identified and classified as a pigmented trichoblastoma. Four cases of melanotrichoblastoma have been reported and represent a variant of a pigmented trichoblastoma characterized by the presence of melanocytes within the lesion. Whether they represent a true variant is of some debate and additional study is required. Although these tumors are exceedingly rare, it is important for the clinician and pathologist to be aware of this entity to prevent confusion with other similarly appearing follicular lesions, most notably BCCs, because of the difference in treatment and follow-up.

Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.¹ Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.² The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.³ A median period of 4 months between time of onset and time of diagnosis has been previously established.⁴

When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,^6,7 which is consistent with current thinking today.

Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.

Case Report

A 93-year-old man was referred to our clinic for treatment of erosive pustular dermatosis of the scalp with photodynamic therapy (PDT). He had a more than 20-year history of multiple skin lesions including basal cell carcinoma, squamous cell carcinoma, and actinic keratoses (AKs). For one year prior to the current presentation the patient had concerns of pustules, scaling, itching, and scabbing on the scalp. The patient admitted that the pruritus caused him to pick at the scabs on the scalp. He had previously been treated with lactic acid 12% neutralized with ammonium hydroxide, tacrolimus, and halobetasol, all to no avail.

On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.

Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.

 

Comment

Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.

The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.

Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.³ Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.

Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.

Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.

Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.¹⁰ Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.

Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.¹ Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.² The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.³ A median period of 4 months between time of onset and time of diagnosis has been previously established.⁴

When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,^6,7 which is consistent with current thinking today.

Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.

Case Report

A 93-year-old man was referred to our clinic for treatment of erosive pustular dermatosis of the scalp with photodynamic therapy (PDT). He had a more than 20-year history of multiple skin lesions including basal cell carcinoma, squamous cell carcinoma, and actinic keratoses (AKs). For one year prior to the current presentation the patient had concerns of pustules, scaling, itching, and scabbing on the scalp. The patient admitted that the pruritus caused him to pick at the scabs on the scalp. He had previously been treated with lactic acid 12% neutralized with ammonium hydroxide, tacrolimus, and halobetasol, all to no avail.

On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.

Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.

 

Comment

Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.

The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.

Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.³ Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.

Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.

Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.

Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.¹⁰ Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.

Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.¹ Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.² The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.³ A median period of 4 months between time of onset and time of diagnosis has been previously established.⁴

When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,^6,7 which is consistent with current thinking today.

Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.

Case Report

A 93-year-old man was referred to our clinic for treatment of erosive pustular dermatosis of the scalp with photodynamic therapy (PDT). He had a more than 20-year history of multiple skin lesions including basal cell carcinoma, squamous cell carcinoma, and actinic keratoses (AKs). For one year prior to the current presentation the patient had concerns of pustules, scaling, itching, and scabbing on the scalp. The patient admitted that the pruritus caused him to pick at the scabs on the scalp. He had previously been treated with lactic acid 12% neutralized with ammonium hydroxide, tacrolimus, and halobetasol, all to no avail.

On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.

Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.

 

Comment

Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.

The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.

Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.³ Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.

Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.

Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.

Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.¹⁰ Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.

NEW YORK – We share more than affection with our dogs and cats. We also share diseases – about which our four-legged furry friends can teach us plenty.

That was the conclusion of speakers at a session on “cases at the intersection of human and veterinary dermatology,” presented at the summer meeting of the American Academy of Dermatology.

“Human health is intimately connected to animal health,” said Jennifer Gardner, MD, of the division of dermatology, University of Washington, Seattle, and a collaborating member of the school’s Center for One Health Research. The One Health framework looks at factors involved in the human, environmental, and animal sectors from the molecular level to the individual level and even to the planetary level.

Dr. Gardner challenged her audience to think beyond their individual areas of expertise. “How does the work you’re doing with a patient or test tube connect up the line and make an impact to levels higher up?” she asked.

The One Health framework also challenges practitioners to look horizontally, at how work done in the human world connects to what’s going on in the veterinary world – that is, how treatments for dermatologic conditions in dogs may one day affect how dermatologists treat the same or similar disorders in humans.

Learning from the mighty mite

For example, the study of mites that live on the skin of animals could eventually shed light on how dermatologists treat mite-related conditions in humans.

Dirk M. Elston, MD, professor and chair of the department of dermatology at the Medical University of South Carolina, Charleston, noted that Demodex mites occur in humans and in pets.

In people, they play a role in papular eruptions in immunosuppressed patients, and in rosacea, alopecia, and blepharitis, he said. Patients with pityriasis folliculorum may look like they have rosacea, “but with little spines” – which are Demodex mites dining in. “They are so crowded in there that their backsides are sticking out,” he said. “They’re all there munching on the sebaceous glands.”

In such cases, “sulfur tends to be my most reliable” treatment, he said, noting that it releases a rotten egg smell. “You’re basically gassing the organism.” Dr. Elston said he frequently gets calls from fellow dermatologists whose antimite efforts have failed with ivermectin and permethrin and does not hesitate to give his advice. “I’m like a broken record,” he said. “Sulfur, sulfur, sulfur, sulfur.”

The Demodex mite affects dogs to varying degrees, depending on where they live, said Kathryn Rook, VMD, of the department of dermatology at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. In North America, demodicosis occurs in 0.38%-0.58% of dogs, and in 25% of dogs in Mexico, she said.

Amitraz, the only Food and Drug Administration–approved treatment for canine demodicosis, is available only as a dip. But it has fallen from favor as a result of sometimes serious side effects, which can include sedation, bradycardia, ataxia, vomiting, diarrhea, and hyperglycemia.

Daily administration of oral ivermectin – often for months – also carries a risk of side effects, including dilated pupils, ataxia, sedation, stupor, coma, hypersalivation, vomiting, diarrhea, blindness, tremors, seizures, and respiratory depression.

Eriklam/Thinkstock

But the discovery of isoxazoline has “revolutionized” the treatment of demodicosis and other parasitic infestations in dogs, Dr. Rook said, citing quicker resolution of disease and improved quality of life for both the patient and its owner.

Isoxazoline, which Dr. Rook said carries little risk for side effects, is licensed in the United States only as a flea and tick preventive.

Atopic dermatitis

Atopic dermatitis (AD) tends to be similar in people and dogs, according to Charles W. Bradley, DVM, of the University of Pennsylvania School of Veterinary Medicine, Philadelphia. About 10%-30% of children and up to 10% of adults have the disorder, the prevalence of which has more than doubled in recent years, he said.

In dogs, the prevalence is 10%-20%, making it “an extraordinarily common disorder,” he said. Lesions tend to be located on the feet, face, pinnae, ventrum, and axilla/inguinum. Additional sites vary by breed, with Dalmatians tending to get AD on the lips, French Bulldogs on the eyelids, German Shepherds on the elbows, Shar-Peis on the thorax, and Boxers on the ears.

In humans, Staphylococcus aureus is the chief microorganism of concern, said Elizabeth Grice, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, who copresented the topic with Dr. Bradley.

Concern about drug resistance is “one reason why we want to better understand the entire microbiome and other organisms that are colonizing the skin,” she commented. That means better understanding the relationship among S. aureus, microbial diversity, and disease severity.

“My true love is anything to do with the skin microbiome,” she said. “The more severe the disease, the lower the skin microbiome diversity.”

Though most studies of AD use mice as animal models, dogs would be better, according to Dr. Grice and Dr. Bradley.

That’s because canine AD occurs spontaneously and exhibits immunologic and clinical features similar to those of human AD. They include prevalence, environmental triggers, immunologic profiles, genetic predispositions, lesion distribution, and frequent colonization by Staphylococcus species. In addition, dogs and their owners tend to share the same environment.

A rash of itches

Among dermatology patients – man or beast – itch can outweigh rash as a key focus of concern, according to Brian Kim, MD, of the division of dermatology at Washington University in St. Louis, and codirector for the University’s Center for the Study of Itch. “The problem is my patients don’t complain about their rash; they complain about their itch,” he said. “But we don’t understand the basic question of itch.” In fact, the FDA has not approved any drugs for the treatment of chronic itch, he said.

Toward that end, veterinary medicine is moving faster than human medicine, he said, citing work in mice that has succeeded in killing itch.

For dogs, advances have been made with Janus kinase (JAK) inhibitors, which “may function as immunomodulators,” Dr. Kim said. And JAK-1 selective inhibition “may be more effective than broad JAK blockade for itch.”

‘The perfect culture plate’

Lessons can be learned from studying canine AD, which “is immunophysiologically homologous to human AD,” said Daniel O. Morris, DVM, MPH, professor of dermatology, at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. “The main difference: My patients are covered in dense hair coats.” Because of that, systemic treatment is necessary, he said.

Canine AD primarily affects areas where hair is sparse or where the surface microclimate is moist, he said. A dog’s ear canal, which can be 10 times longer than a human’s, harbors plenty of moisture and heat, he said. “It’s the perfect culture plate.”

But, he added, the owners of his patients tend to resist using topical therapies “that could be potentially smeared on the babies and grandma’s diabetic foot ulcer.” So he has long relied on systemic treatments, initially steroids and cyclosporine. But they can have major side effects, and cyclosporine can take 60-90 days before it exerts maximum effect.

A faster-acting compound called oclacitinib has shown promise based on its high affinity for inhibiting JAK-1 enzyme-mediated activation of cytokine expression, including interleukin (IL)-31, he said. “Clinical trials demonstrate an antipruritic efficacy equivalent to both prednisolone and cyclosporine,” he noted. Contraindications include a history of neoplasia, the presence of severe infection, and age under 1 year.

Monoclonal antibody targets IL-31

The latest promising arrival is lokivetmab, a monoclonal antibody that targets canine IL-31, according to Dr. Morris. It acts rapidly (within 1 day for many dogs) and prevents binding of IL-31 to its neuronal receptor for at least a month, thereby interrupting neurotransmission of itch.

But side effects can be serious and common. Equal efficacy with a reduced side effect is the holy grail, he said.

Some doctors are not waiting. “People are throwing these two products at anything that itches,” he said. Unfortunately, they tend to “work miserably” for causes other than AD, he added.

Dr. Gardner, Dr. Elston, Dr. Rook, Dr. Bradley, and Dr. Morris reported no financial conflicts. Dr. Grice’s disclosures include having served as a speaker for GlaxoSmithKline and for L’Oreal France, and having received grants/research funding from Janssen Research & Development. Dr. Kim has served as a consultant to biotechnology and pharmaceutical companies.

NEW YORK – We share more than affection with our dogs and cats. We also share diseases – about which our four-legged furry friends can teach us plenty.

That was the conclusion of speakers at a session on “cases at the intersection of human and veterinary dermatology,” presented at the summer meeting of the American Academy of Dermatology.

“Human health is intimately connected to animal health,” said Jennifer Gardner, MD, of the division of dermatology, University of Washington, Seattle, and a collaborating member of the school’s Center for One Health Research. The One Health framework looks at factors involved in the human, environmental, and animal sectors from the molecular level to the individual level and even to the planetary level.

Dr. Gardner challenged her audience to think beyond their individual areas of expertise. “How does the work you’re doing with a patient or test tube connect up the line and make an impact to levels higher up?” she asked.

The One Health framework also challenges practitioners to look horizontally, at how work done in the human world connects to what’s going on in the veterinary world – that is, how treatments for dermatologic conditions in dogs may one day affect how dermatologists treat the same or similar disorders in humans.

Learning from the mighty mite

For example, the study of mites that live on the skin of animals could eventually shed light on how dermatologists treat mite-related conditions in humans.

Dirk M. Elston, MD, professor and chair of the department of dermatology at the Medical University of South Carolina, Charleston, noted that Demodex mites occur in humans and in pets.

In people, they play a role in papular eruptions in immunosuppressed patients, and in rosacea, alopecia, and blepharitis, he said. Patients with pityriasis folliculorum may look like they have rosacea, “but with little spines” – which are Demodex mites dining in. “They are so crowded in there that their backsides are sticking out,” he said. “They’re all there munching on the sebaceous glands.”

In such cases, “sulfur tends to be my most reliable” treatment, he said, noting that it releases a rotten egg smell. “You’re basically gassing the organism.” Dr. Elston said he frequently gets calls from fellow dermatologists whose antimite efforts have failed with ivermectin and permethrin and does not hesitate to give his advice. “I’m like a broken record,” he said. “Sulfur, sulfur, sulfur, sulfur.”

The Demodex mite affects dogs to varying degrees, depending on where they live, said Kathryn Rook, VMD, of the department of dermatology at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. In North America, demodicosis occurs in 0.38%-0.58% of dogs, and in 25% of dogs in Mexico, she said.

Amitraz, the only Food and Drug Administration–approved treatment for canine demodicosis, is available only as a dip. But it has fallen from favor as a result of sometimes serious side effects, which can include sedation, bradycardia, ataxia, vomiting, diarrhea, and hyperglycemia.

Daily administration of oral ivermectin – often for months – also carries a risk of side effects, including dilated pupils, ataxia, sedation, stupor, coma, hypersalivation, vomiting, diarrhea, blindness, tremors, seizures, and respiratory depression.

Eriklam/Thinkstock

But the discovery of isoxazoline has “revolutionized” the treatment of demodicosis and other parasitic infestations in dogs, Dr. Rook said, citing quicker resolution of disease and improved quality of life for both the patient and its owner.

Isoxazoline, which Dr. Rook said carries little risk for side effects, is licensed in the United States only as a flea and tick preventive.

Atopic dermatitis

Atopic dermatitis (AD) tends to be similar in people and dogs, according to Charles W. Bradley, DVM, of the University of Pennsylvania School of Veterinary Medicine, Philadelphia. About 10%-30% of children and up to 10% of adults have the disorder, the prevalence of which has more than doubled in recent years, he said.

In dogs, the prevalence is 10%-20%, making it “an extraordinarily common disorder,” he said. Lesions tend to be located on the feet, face, pinnae, ventrum, and axilla/inguinum. Additional sites vary by breed, with Dalmatians tending to get AD on the lips, French Bulldogs on the eyelids, German Shepherds on the elbows, Shar-Peis on the thorax, and Boxers on the ears.

In humans, Staphylococcus aureus is the chief microorganism of concern, said Elizabeth Grice, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, who copresented the topic with Dr. Bradley.

Concern about drug resistance is “one reason why we want to better understand the entire microbiome and other organisms that are colonizing the skin,” she commented. That means better understanding the relationship among S. aureus, microbial diversity, and disease severity.

“My true love is anything to do with the skin microbiome,” she said. “The more severe the disease, the lower the skin microbiome diversity.”

Though most studies of AD use mice as animal models, dogs would be better, according to Dr. Grice and Dr. Bradley.

That’s because canine AD occurs spontaneously and exhibits immunologic and clinical features similar to those of human AD. They include prevalence, environmental triggers, immunologic profiles, genetic predispositions, lesion distribution, and frequent colonization by Staphylococcus species. In addition, dogs and their owners tend to share the same environment.

A rash of itches

Among dermatology patients – man or beast – itch can outweigh rash as a key focus of concern, according to Brian Kim, MD, of the division of dermatology at Washington University in St. Louis, and codirector for the University’s Center for the Study of Itch. “The problem is my patients don’t complain about their rash; they complain about their itch,” he said. “But we don’t understand the basic question of itch.” In fact, the FDA has not approved any drugs for the treatment of chronic itch, he said.

Toward that end, veterinary medicine is moving faster than human medicine, he said, citing work in mice that has succeeded in killing itch.

For dogs, advances have been made with Janus kinase (JAK) inhibitors, which “may function as immunomodulators,” Dr. Kim said. And JAK-1 selective inhibition “may be more effective than broad JAK blockade for itch.”

‘The perfect culture plate’

Lessons can be learned from studying canine AD, which “is immunophysiologically homologous to human AD,” said Daniel O. Morris, DVM, MPH, professor of dermatology, at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. “The main difference: My patients are covered in dense hair coats.” Because of that, systemic treatment is necessary, he said.

Canine AD primarily affects areas where hair is sparse or where the surface microclimate is moist, he said. A dog’s ear canal, which can be 10 times longer than a human’s, harbors plenty of moisture and heat, he said. “It’s the perfect culture plate.”

But, he added, the owners of his patients tend to resist using topical therapies “that could be potentially smeared on the babies and grandma’s diabetic foot ulcer.” So he has long relied on systemic treatments, initially steroids and cyclosporine. But they can have major side effects, and cyclosporine can take 60-90 days before it exerts maximum effect.

A faster-acting compound called oclacitinib has shown promise based on its high affinity for inhibiting JAK-1 enzyme-mediated activation of cytokine expression, including interleukin (IL)-31, he said. “Clinical trials demonstrate an antipruritic efficacy equivalent to both prednisolone and cyclosporine,” he noted. Contraindications include a history of neoplasia, the presence of severe infection, and age under 1 year.

Monoclonal antibody targets IL-31

The latest promising arrival is lokivetmab, a monoclonal antibody that targets canine IL-31, according to Dr. Morris. It acts rapidly (within 1 day for many dogs) and prevents binding of IL-31 to its neuronal receptor for at least a month, thereby interrupting neurotransmission of itch.

But side effects can be serious and common. Equal efficacy with a reduced side effect is the holy grail, he said.

Some doctors are not waiting. “People are throwing these two products at anything that itches,” he said. Unfortunately, they tend to “work miserably” for causes other than AD, he added.

Dr. Gardner, Dr. Elston, Dr. Rook, Dr. Bradley, and Dr. Morris reported no financial conflicts. Dr. Grice’s disclosures include having served as a speaker for GlaxoSmithKline and for L’Oreal France, and having received grants/research funding from Janssen Research & Development. Dr. Kim has served as a consultant to biotechnology and pharmaceutical companies.

NEW YORK – We share more than affection with our dogs and cats. We also share diseases – about which our four-legged furry friends can teach us plenty.

That was the conclusion of speakers at a session on “cases at the intersection of human and veterinary dermatology,” presented at the summer meeting of the American Academy of Dermatology.

“Human health is intimately connected to animal health,” said Jennifer Gardner, MD, of the division of dermatology, University of Washington, Seattle, and a collaborating member of the school’s Center for One Health Research. The One Health framework looks at factors involved in the human, environmental, and animal sectors from the molecular level to the individual level and even to the planetary level.

Dr. Gardner challenged her audience to think beyond their individual areas of expertise. “How does the work you’re doing with a patient or test tube connect up the line and make an impact to levels higher up?” she asked.

The One Health framework also challenges practitioners to look horizontally, at how work done in the human world connects to what’s going on in the veterinary world – that is, how treatments for dermatologic conditions in dogs may one day affect how dermatologists treat the same or similar disorders in humans.

Learning from the mighty mite

For example, the study of mites that live on the skin of animals could eventually shed light on how dermatologists treat mite-related conditions in humans.

Dirk M. Elston, MD, professor and chair of the department of dermatology at the Medical University of South Carolina, Charleston, noted that Demodex mites occur in humans and in pets.

In people, they play a role in papular eruptions in immunosuppressed patients, and in rosacea, alopecia, and blepharitis, he said. Patients with pityriasis folliculorum may look like they have rosacea, “but with little spines” – which are Demodex mites dining in. “They are so crowded in there that their backsides are sticking out,” he said. “They’re all there munching on the sebaceous glands.”

In such cases, “sulfur tends to be my most reliable” treatment, he said, noting that it releases a rotten egg smell. “You’re basically gassing the organism.” Dr. Elston said he frequently gets calls from fellow dermatologists whose antimite efforts have failed with ivermectin and permethrin and does not hesitate to give his advice. “I’m like a broken record,” he said. “Sulfur, sulfur, sulfur, sulfur.”

The Demodex mite affects dogs to varying degrees, depending on where they live, said Kathryn Rook, VMD, of the department of dermatology at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. In North America, demodicosis occurs in 0.38%-0.58% of dogs, and in 25% of dogs in Mexico, she said.

Amitraz, the only Food and Drug Administration–approved treatment for canine demodicosis, is available only as a dip. But it has fallen from favor as a result of sometimes serious side effects, which can include sedation, bradycardia, ataxia, vomiting, diarrhea, and hyperglycemia.

Daily administration of oral ivermectin – often for months – also carries a risk of side effects, including dilated pupils, ataxia, sedation, stupor, coma, hypersalivation, vomiting, diarrhea, blindness, tremors, seizures, and respiratory depression.

Eriklam/Thinkstock

But the discovery of isoxazoline has “revolutionized” the treatment of demodicosis and other parasitic infestations in dogs, Dr. Rook said, citing quicker resolution of disease and improved quality of life for both the patient and its owner.

Isoxazoline, which Dr. Rook said carries little risk for side effects, is licensed in the United States only as a flea and tick preventive.

Atopic dermatitis

Atopic dermatitis (AD) tends to be similar in people and dogs, according to Charles W. Bradley, DVM, of the University of Pennsylvania School of Veterinary Medicine, Philadelphia. About 10%-30% of children and up to 10% of adults have the disorder, the prevalence of which has more than doubled in recent years, he said.

In dogs, the prevalence is 10%-20%, making it “an extraordinarily common disorder,” he said. Lesions tend to be located on the feet, face, pinnae, ventrum, and axilla/inguinum. Additional sites vary by breed, with Dalmatians tending to get AD on the lips, French Bulldogs on the eyelids, German Shepherds on the elbows, Shar-Peis on the thorax, and Boxers on the ears.

In humans, Staphylococcus aureus is the chief microorganism of concern, said Elizabeth Grice, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, who copresented the topic with Dr. Bradley.

Concern about drug resistance is “one reason why we want to better understand the entire microbiome and other organisms that are colonizing the skin,” she commented. That means better understanding the relationship among S. aureus, microbial diversity, and disease severity.

“My true love is anything to do with the skin microbiome,” she said. “The more severe the disease, the lower the skin microbiome diversity.”

Though most studies of AD use mice as animal models, dogs would be better, according to Dr. Grice and Dr. Bradley.

That’s because canine AD occurs spontaneously and exhibits immunologic and clinical features similar to those of human AD. They include prevalence, environmental triggers, immunologic profiles, genetic predispositions, lesion distribution, and frequent colonization by Staphylococcus species. In addition, dogs and their owners tend to share the same environment.

A rash of itches

Among dermatology patients – man or beast – itch can outweigh rash as a key focus of concern, according to Brian Kim, MD, of the division of dermatology at Washington University in St. Louis, and codirector for the University’s Center for the Study of Itch. “The problem is my patients don’t complain about their rash; they complain about their itch,” he said. “But we don’t understand the basic question of itch.” In fact, the FDA has not approved any drugs for the treatment of chronic itch, he said.

Toward that end, veterinary medicine is moving faster than human medicine, he said, citing work in mice that has succeeded in killing itch.

For dogs, advances have been made with Janus kinase (JAK) inhibitors, which “may function as immunomodulators,” Dr. Kim said. And JAK-1 selective inhibition “may be more effective than broad JAK blockade for itch.”

‘The perfect culture plate’

Lessons can be learned from studying canine AD, which “is immunophysiologically homologous to human AD,” said Daniel O. Morris, DVM, MPH, professor of dermatology, at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. “The main difference: My patients are covered in dense hair coats.” Because of that, systemic treatment is necessary, he said.

Canine AD primarily affects areas where hair is sparse or where the surface microclimate is moist, he said. A dog’s ear canal, which can be 10 times longer than a human’s, harbors plenty of moisture and heat, he said. “It’s the perfect culture plate.”

But, he added, the owners of his patients tend to resist using topical therapies “that could be potentially smeared on the babies and grandma’s diabetic foot ulcer.” So he has long relied on systemic treatments, initially steroids and cyclosporine. But they can have major side effects, and cyclosporine can take 60-90 days before it exerts maximum effect.

A faster-acting compound called oclacitinib has shown promise based on its high affinity for inhibiting JAK-1 enzyme-mediated activation of cytokine expression, including interleukin (IL)-31, he said. “Clinical trials demonstrate an antipruritic efficacy equivalent to both prednisolone and cyclosporine,” he noted. Contraindications include a history of neoplasia, the presence of severe infection, and age under 1 year.

Monoclonal antibody targets IL-31

The latest promising arrival is lokivetmab, a monoclonal antibody that targets canine IL-31, according to Dr. Morris. It acts rapidly (within 1 day for many dogs) and prevents binding of IL-31 to its neuronal receptor for at least a month, thereby interrupting neurotransmission of itch.

But side effects can be serious and common. Equal efficacy with a reduced side effect is the holy grail, he said.

Some doctors are not waiting. “People are throwing these two products at anything that itches,” he said. Unfortunately, they tend to “work miserably” for causes other than AD, he added.

Dr. Gardner, Dr. Elston, Dr. Rook, Dr. Bradley, and Dr. Morris reported no financial conflicts. Dr. Grice’s disclosures include having served as a speaker for GlaxoSmithKline and for L’Oreal France, and having received grants/research funding from Janssen Research & Development. Dr. Kim has served as a consultant to biotechnology and pharmaceutical companies.

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹