Case Letter

To the Editor:

Vitiligolike depigmentation has been known to develop around the sites of origin of melanoma or more rarely in patients treated with antimelanoma therapy.¹ Vitiligo is characterized by white patchy depigmentation of the skin caused by the loss of functional melanocytes from the epidermis. The exact mechanisms of disease are unknown and multifactorial; however, autoimmunity plays a central role. Interferon gamma (IFN-γ), C-X-C chemokine ligand 10, and IL-22 have been identified as key mediators in an inflammatory cascade leading to the stimulation of the innate immune response against melanocyte antigens.^2,3 Research suggests melanoma-associated vitiligolike leukoderma also results from an immune reaction directed against antigenic determinants shared by both normal and malignant melanocytes.³ Vitiligolike lesions have been associated with the use of immunomodulatory agents such as nivolumab, a fully humanized monoclonal IgG4 antibody, which blocks the programmed cell death protein 1 (PD-1) receptor that normally is expressed on T cells during the effector phase of T-cell activation.^4,5 In the tumor microenvironment, the PD-1 receptor is stimulated, leading to downregulation of the T-cell effector function and destruction of T cells.⁵ Due to T-cell apoptosis and consequent suppression of the immune response, tumorigenesis continues. By inhibiting the PD-1 receptor, nivolumab increases the number of active T cells and antitumor response. However, the distressing side effect of vitiligolike depigmentation has been reported in 15% to 25% of treated patients.⁶

In a meta-analysis by Teulings et al,⁷ patients with new-onset vitiligo and malignant melanoma demonstrated a 2-fold decrease in cancer progression and a 4-fold decreased risk for death vs patients without vitiligo development. Thus, in patients with melanoma, vitiligolike depigmentation should be considered a good prognostic indicator as well as a visible sign of spontaneous or therapy-induced antihumoral immune response against melanocyte differentiation antigens, as it is associated with a notable survival benefit in patients receiving immunotherapy for metastatic melanoma.³ We describe a case of diffuse vitiligolike depigmentation that developed suddenly during nivolumab treatment, causing much distress to the patient.

A 75-year-old woman presented to the clinic with a chief concern of sudden diffuse skin discoloration primarily affecting the face, hands, and extremities of 3 weeks’ duration. She had a medical history of metastatic melanoma—the site of the primary melanoma was never identified—and she was undergoing immune-modulating therapy with nivolumab. She was on her fifth month of treatment and was experiencing a robust therapeutic response with a reported 100% clearance of the metastatic melanoma as observed on a positron emission tomography scan. The patchy depigmentation of skin was causing her much distress. Physical examination revealed diffuse patches of hypopigmentation on the trunk, face, and extremities (Figure). Shave biopsies of the right lateral arm demonstrated changes consistent with vitiligo, with an adjacent biopsy illustrating normal skin characteristics. Triamcinolone ointment 0.1% was initiated, with instruction to apply it to affected areas twice daily for 2 weeks. However, there was no improvement, and she discontinued use.

At 3-month follow-up, the depigmentation persisted, prompting a trial of hydroquinone cream 4% to be used sparingly in cosmetically sensitive areas such as the face and dorsal aspects of the hands. Additionally, diligent photoprotection was advised. Upon re-evaluation 9 months later, the patient remained in cancer remission, continued nivolumab therapy, and reported improvement in the hypopigmentation with a more even skin color with topical hydroquinone use. She no longer noticed starkly contrasting hypopigmented patches.

Vitiligo is a benign skin condition characterized by white depigmented macules and patches. The key feature of the disorder is loss of functional melanocytes from the cutaneous epidermis and sometimes from the hair follicles, with various theories on the cause. It has been suggested that the disease is multifactorial, involving both genetics and environmental factors.² Regardless of the exact mechanism, the result is always the same: loss of melanin pigment in cells due to loss of melanocytes.

Autoimmunity plays a central role in the causation of vitiligo and was first suspected as a possible cause due to the association of vitiligo with several other autoimmune disorders, such as thyroiditis.⁸ An epidemiological survey from the United Kingdom and North America (N=2624) found that 19.4% of vitiligo patients aged 20 years or older also reported a clinical history of autoimmune thyroid disease compared with 2.4% of the overall White population of the same age.⁹ Interferon gamma, C-X-C chemokine ligand 10, and IL-22 receptors stimulate the innate immune response, resulting in an overactive danger signaling cascade, which leads to proinflammatory signals against melanocyte antigens.^2,3 The adaptive immune system also participates in the progression of vitiligo by activating dermal dendritic cells to attack melanocytes along with melanocyte-specific cytotoxic T cells.

Immunomodulatory agents utilized in the treatment of metastatic melanoma have been linked to vitiligolike depigmentation. In those receiving PD-1 immunotherapy for metastatic melanoma, vitiligolike lesions have been reported in 15% to 25% of patients.⁶ Typically, the PD-1 molecule has a regulatory function on effector T cells. Interaction of the PD-1 receptor with its ligands occurs primarily in peripheral tissue causing apoptosis and downregulation of effector T cells with the goal of decreasing collateral damage to surrounding tissues by active T cells.⁵ In the tumor microenvironment, however, suppression of the host’s immune response is enhanced by aberrant stimulation of the PD-1 receptor, causing downregulation of the T-cell effector function, T-cell destruction, and apoptosis, which results in continued tumor growth. Nivolumab, a fully humanized monoclonal IgG4 antibody, selectively inhibits the PD-1 receptor, disrupting the regulator pathway that would typically end in T-cell destruction.⁵ Accordingly, the population of active T cells is increased along with the antitumor response.^4,10 Nivolumab exhibits success as an immunotherapeutic agent, with an overall survival rate in patients with metastatic melanoma undergoing nivolumab therapy of 41% to 42% at 3 years and 35% at 5 years.¹¹ However, therapeutic manipulation of the host’s immune response does not come without a cost. Vitiligolike lesions have been reported in up to a quarter of patients receiving PD-1 immunotherapy for metastatic melanoma.⁶

 

The relationship between vitiligolike depigmentation and melanoma can be explained by the immune activation against antigens associated with melanoma that also are expressed by normal melanocytes. In clinical observations of patients with melanoma and patients with vitiligo, antibodies to human melanocyte antigens were present in 80% (24/30) of patients vs 7% (2/28) in the control group.¹² The autoimmune response results from a cross-reaction of melanoma cells that share the same antigens as normal melanocytes, such as melanoma antigen recognized by T cells 1 (MART-1), gp100, and tyrosinase.^13,14

Development of vitiligolike depigmentation in patients with metastatic melanoma treated with nivolumab has been reported to occur between 2 and 15 months after the start of PD-1 therapy. This side effect of treatment correlates with favorable clinical outcomes.^15,16 Enhancing immune recognition of melanocytes in patients with melanoma confers a survival advantage, as studies by Koh et al¹⁷ and Norlund et al¹⁸ involving patients who developed vitiligolike hypopigmentation associated with malignant melanoma indicated a better prognosis than for those without hypopigmentation. The 5-year survival rate of patients with both malignant melanoma and vitiligo was reported as 60% to 67% when it was estimated that only 30% to 50% of patients should have survived that duration of time.^17,18 Similarly, a systematic review of patients with melanoma stages III and IV reported that those with associated hypopigmentation had a 2- to 4-fold decreased risk of disease progression and death compared to patients without depigmentation.⁷

Use of traditional treatment therapies for vitiligo is based on the ability of the therapy to suppress the immune system. However, in patients with metastatic melanoma undergoing immune-modulating cancer therapies, traditional treatment options may counter the antitumor effects of the targeted immunotherapies and should be used with caution. Our patient displayed improvement in the appearance of her starkly contrasting hypopigmented patches with the use of hydroquinone cream 4%, which induced necrotic death of melanocytes by inhibiting the conversion of L-3,4-dihydroxyphenylalanine to melanin by tyrosinase.¹⁹ The effect achieved by using topical hydroquinone 4% was a lighter skin appearance in areas of application.

There is no cure for vitiligo, and although it is a benign condition, it can negatively impact a patient's quality of life. In some countries, vitiligo is confused with leprosy, resulting in a social stigma attached to the diagnosis. Many patients are frightened or embarrassed by the diagnosis of vitiligo and its effects, and they often experience discrimination.² Patients with vitiligo also experience more psychological difficulties such as depression.²⁰ The unpredictability of vitiligo is associated with negative emotions including fear of spreading the lesions, shame, insecurity, and sadness.²¹ Supportive care measures, including psychological support and counseling, are recommended. Additionally, upon initiation of anti–PD-1 therapies, expectations should be discussed with patients concerning the possibilities of depigmentation and associated treatment results. Although the occurrence of vitiligo may cause the patient concern, it should be communicated that its presence is a positive indicator of a vigorous antimelanoma immunity and an increased survival rate.⁷

Vitiligolike depigmentation is a known rare adverse effect of nivolumab treatment. Although aesthetically unfavorable for the patient, the development of vitiligolike lesions while undergoing immunotherapy for melanoma may be a sign of a promising clinical outcome due to an effective immune response to melanoma antigens. Our patient remains in remission without any evidence of melanoma after 9 months of therapy, which offers support for a promising outcome for melanoma patients who experience vitiligolike depigmentation.

To the Editor:

Vitiligolike depigmentation has been known to develop around the sites of origin of melanoma or more rarely in patients treated with antimelanoma therapy.¹ Vitiligo is characterized by white patchy depigmentation of the skin caused by the loss of functional melanocytes from the epidermis. The exact mechanisms of disease are unknown and multifactorial; however, autoimmunity plays a central role. Interferon gamma (IFN-γ), C-X-C chemokine ligand 10, and IL-22 have been identified as key mediators in an inflammatory cascade leading to the stimulation of the innate immune response against melanocyte antigens.^2,3 Research suggests melanoma-associated vitiligolike leukoderma also results from an immune reaction directed against antigenic determinants shared by both normal and malignant melanocytes.³ Vitiligolike lesions have been associated with the use of immunomodulatory agents such as nivolumab, a fully humanized monoclonal IgG4 antibody, which blocks the programmed cell death protein 1 (PD-1) receptor that normally is expressed on T cells during the effector phase of T-cell activation.^4,5 In the tumor microenvironment, the PD-1 receptor is stimulated, leading to downregulation of the T-cell effector function and destruction of T cells.⁵ Due to T-cell apoptosis and consequent suppression of the immune response, tumorigenesis continues. By inhibiting the PD-1 receptor, nivolumab increases the number of active T cells and antitumor response. However, the distressing side effect of vitiligolike depigmentation has been reported in 15% to 25% of treated patients.⁶

In a meta-analysis by Teulings et al,⁷ patients with new-onset vitiligo and malignant melanoma demonstrated a 2-fold decrease in cancer progression and a 4-fold decreased risk for death vs patients without vitiligo development. Thus, in patients with melanoma, vitiligolike depigmentation should be considered a good prognostic indicator as well as a visible sign of spontaneous or therapy-induced antihumoral immune response against melanocyte differentiation antigens, as it is associated with a notable survival benefit in patients receiving immunotherapy for metastatic melanoma.³ We describe a case of diffuse vitiligolike depigmentation that developed suddenly during nivolumab treatment, causing much distress to the patient.

A 75-year-old woman presented to the clinic with a chief concern of sudden diffuse skin discoloration primarily affecting the face, hands, and extremities of 3 weeks’ duration. She had a medical history of metastatic melanoma—the site of the primary melanoma was never identified—and she was undergoing immune-modulating therapy with nivolumab. She was on her fifth month of treatment and was experiencing a robust therapeutic response with a reported 100% clearance of the metastatic melanoma as observed on a positron emission tomography scan. The patchy depigmentation of skin was causing her much distress. Physical examination revealed diffuse patches of hypopigmentation on the trunk, face, and extremities (Figure). Shave biopsies of the right lateral arm demonstrated changes consistent with vitiligo, with an adjacent biopsy illustrating normal skin characteristics. Triamcinolone ointment 0.1% was initiated, with instruction to apply it to affected areas twice daily for 2 weeks. However, there was no improvement, and she discontinued use.

At 3-month follow-up, the depigmentation persisted, prompting a trial of hydroquinone cream 4% to be used sparingly in cosmetically sensitive areas such as the face and dorsal aspects of the hands. Additionally, diligent photoprotection was advised. Upon re-evaluation 9 months later, the patient remained in cancer remission, continued nivolumab therapy, and reported improvement in the hypopigmentation with a more even skin color with topical hydroquinone use. She no longer noticed starkly contrasting hypopigmented patches.

Vitiligo is a benign skin condition characterized by white depigmented macules and patches. The key feature of the disorder is loss of functional melanocytes from the cutaneous epidermis and sometimes from the hair follicles, with various theories on the cause. It has been suggested that the disease is multifactorial, involving both genetics and environmental factors.² Regardless of the exact mechanism, the result is always the same: loss of melanin pigment in cells due to loss of melanocytes.

Autoimmunity plays a central role in the causation of vitiligo and was first suspected as a possible cause due to the association of vitiligo with several other autoimmune disorders, such as thyroiditis.⁸ An epidemiological survey from the United Kingdom and North America (N=2624) found that 19.4% of vitiligo patients aged 20 years or older also reported a clinical history of autoimmune thyroid disease compared with 2.4% of the overall White population of the same age.⁹ Interferon gamma, C-X-C chemokine ligand 10, and IL-22 receptors stimulate the innate immune response, resulting in an overactive danger signaling cascade, which leads to proinflammatory signals against melanocyte antigens.^2,3 The adaptive immune system also participates in the progression of vitiligo by activating dermal dendritic cells to attack melanocytes along with melanocyte-specific cytotoxic T cells.

Immunomodulatory agents utilized in the treatment of metastatic melanoma have been linked to vitiligolike depigmentation. In those receiving PD-1 immunotherapy for metastatic melanoma, vitiligolike lesions have been reported in 15% to 25% of patients.⁶ Typically, the PD-1 molecule has a regulatory function on effector T cells. Interaction of the PD-1 receptor with its ligands occurs primarily in peripheral tissue causing apoptosis and downregulation of effector T cells with the goal of decreasing collateral damage to surrounding tissues by active T cells.⁵ In the tumor microenvironment, however, suppression of the host’s immune response is enhanced by aberrant stimulation of the PD-1 receptor, causing downregulation of the T-cell effector function, T-cell destruction, and apoptosis, which results in continued tumor growth. Nivolumab, a fully humanized monoclonal IgG4 antibody, selectively inhibits the PD-1 receptor, disrupting the regulator pathway that would typically end in T-cell destruction.⁵ Accordingly, the population of active T cells is increased along with the antitumor response.^4,10 Nivolumab exhibits success as an immunotherapeutic agent, with an overall survival rate in patients with metastatic melanoma undergoing nivolumab therapy of 41% to 42% at 3 years and 35% at 5 years.¹¹ However, therapeutic manipulation of the host’s immune response does not come without a cost. Vitiligolike lesions have been reported in up to a quarter of patients receiving PD-1 immunotherapy for metastatic melanoma.⁶

 

The relationship between vitiligolike depigmentation and melanoma can be explained by the immune activation against antigens associated with melanoma that also are expressed by normal melanocytes. In clinical observations of patients with melanoma and patients with vitiligo, antibodies to human melanocyte antigens were present in 80% (24/30) of patients vs 7% (2/28) in the control group.¹² The autoimmune response results from a cross-reaction of melanoma cells that share the same antigens as normal melanocytes, such as melanoma antigen recognized by T cells 1 (MART-1), gp100, and tyrosinase.^13,14

Development of vitiligolike depigmentation in patients with metastatic melanoma treated with nivolumab has been reported to occur between 2 and 15 months after the start of PD-1 therapy. This side effect of treatment correlates with favorable clinical outcomes.^15,16 Enhancing immune recognition of melanocytes in patients with melanoma confers a survival advantage, as studies by Koh et al¹⁷ and Norlund et al¹⁸ involving patients who developed vitiligolike hypopigmentation associated with malignant melanoma indicated a better prognosis than for those without hypopigmentation. The 5-year survival rate of patients with both malignant melanoma and vitiligo was reported as 60% to 67% when it was estimated that only 30% to 50% of patients should have survived that duration of time.^17,18 Similarly, a systematic review of patients with melanoma stages III and IV reported that those with associated hypopigmentation had a 2- to 4-fold decreased risk of disease progression and death compared to patients without depigmentation.⁷

Use of traditional treatment therapies for vitiligo is based on the ability of the therapy to suppress the immune system. However, in patients with metastatic melanoma undergoing immune-modulating cancer therapies, traditional treatment options may counter the antitumor effects of the targeted immunotherapies and should be used with caution. Our patient displayed improvement in the appearance of her starkly contrasting hypopigmented patches with the use of hydroquinone cream 4%, which induced necrotic death of melanocytes by inhibiting the conversion of L-3,4-dihydroxyphenylalanine to melanin by tyrosinase.¹⁹ The effect achieved by using topical hydroquinone 4% was a lighter skin appearance in areas of application.

There is no cure for vitiligo, and although it is a benign condition, it can negatively impact a patient's quality of life. In some countries, vitiligo is confused with leprosy, resulting in a social stigma attached to the diagnosis. Many patients are frightened or embarrassed by the diagnosis of vitiligo and its effects, and they often experience discrimination.² Patients with vitiligo also experience more psychological difficulties such as depression.²⁰ The unpredictability of vitiligo is associated with negative emotions including fear of spreading the lesions, shame, insecurity, and sadness.²¹ Supportive care measures, including psychological support and counseling, are recommended. Additionally, upon initiation of anti–PD-1 therapies, expectations should be discussed with patients concerning the possibilities of depigmentation and associated treatment results. Although the occurrence of vitiligo may cause the patient concern, it should be communicated that its presence is a positive indicator of a vigorous antimelanoma immunity and an increased survival rate.⁷

Vitiligolike depigmentation is a known rare adverse effect of nivolumab treatment. Although aesthetically unfavorable for the patient, the development of vitiligolike lesions while undergoing immunotherapy for melanoma may be a sign of a promising clinical outcome due to an effective immune response to melanoma antigens. Our patient remains in remission without any evidence of melanoma after 9 months of therapy, which offers support for a promising outcome for melanoma patients who experience vitiligolike depigmentation.

To the Editor:

Vitiligolike depigmentation has been known to develop around the sites of origin of melanoma or more rarely in patients treated with antimelanoma therapy.¹ Vitiligo is characterized by white patchy depigmentation of the skin caused by the loss of functional melanocytes from the epidermis. The exact mechanisms of disease are unknown and multifactorial; however, autoimmunity plays a central role. Interferon gamma (IFN-γ), C-X-C chemokine ligand 10, and IL-22 have been identified as key mediators in an inflammatory cascade leading to the stimulation of the innate immune response against melanocyte antigens.^2,3 Research suggests melanoma-associated vitiligolike leukoderma also results from an immune reaction directed against antigenic determinants shared by both normal and malignant melanocytes.³ Vitiligolike lesions have been associated with the use of immunomodulatory agents such as nivolumab, a fully humanized monoclonal IgG4 antibody, which blocks the programmed cell death protein 1 (PD-1) receptor that normally is expressed on T cells during the effector phase of T-cell activation.^4,5 In the tumor microenvironment, the PD-1 receptor is stimulated, leading to downregulation of the T-cell effector function and destruction of T cells.⁵ Due to T-cell apoptosis and consequent suppression of the immune response, tumorigenesis continues. By inhibiting the PD-1 receptor, nivolumab increases the number of active T cells and antitumor response. However, the distressing side effect of vitiligolike depigmentation has been reported in 15% to 25% of treated patients.⁶

In a meta-analysis by Teulings et al,⁷ patients with new-onset vitiligo and malignant melanoma demonstrated a 2-fold decrease in cancer progression and a 4-fold decreased risk for death vs patients without vitiligo development. Thus, in patients with melanoma, vitiligolike depigmentation should be considered a good prognostic indicator as well as a visible sign of spontaneous or therapy-induced antihumoral immune response against melanocyte differentiation antigens, as it is associated with a notable survival benefit in patients receiving immunotherapy for metastatic melanoma.³ We describe a case of diffuse vitiligolike depigmentation that developed suddenly during nivolumab treatment, causing much distress to the patient.

A 75-year-old woman presented to the clinic with a chief concern of sudden diffuse skin discoloration primarily affecting the face, hands, and extremities of 3 weeks’ duration. She had a medical history of metastatic melanoma—the site of the primary melanoma was never identified—and she was undergoing immune-modulating therapy with nivolumab. She was on her fifth month of treatment and was experiencing a robust therapeutic response with a reported 100% clearance of the metastatic melanoma as observed on a positron emission tomography scan. The patchy depigmentation of skin was causing her much distress. Physical examination revealed diffuse patches of hypopigmentation on the trunk, face, and extremities (Figure). Shave biopsies of the right lateral arm demonstrated changes consistent with vitiligo, with an adjacent biopsy illustrating normal skin characteristics. Triamcinolone ointment 0.1% was initiated, with instruction to apply it to affected areas twice daily for 2 weeks. However, there was no improvement, and she discontinued use.

At 3-month follow-up, the depigmentation persisted, prompting a trial of hydroquinone cream 4% to be used sparingly in cosmetically sensitive areas such as the face and dorsal aspects of the hands. Additionally, diligent photoprotection was advised. Upon re-evaluation 9 months later, the patient remained in cancer remission, continued nivolumab therapy, and reported improvement in the hypopigmentation with a more even skin color with topical hydroquinone use. She no longer noticed starkly contrasting hypopigmented patches.

Vitiligo is a benign skin condition characterized by white depigmented macules and patches. The key feature of the disorder is loss of functional melanocytes from the cutaneous epidermis and sometimes from the hair follicles, with various theories on the cause. It has been suggested that the disease is multifactorial, involving both genetics and environmental factors.² Regardless of the exact mechanism, the result is always the same: loss of melanin pigment in cells due to loss of melanocytes.

Autoimmunity plays a central role in the causation of vitiligo and was first suspected as a possible cause due to the association of vitiligo with several other autoimmune disorders, such as thyroiditis.⁸ An epidemiological survey from the United Kingdom and North America (N=2624) found that 19.4% of vitiligo patients aged 20 years or older also reported a clinical history of autoimmune thyroid disease compared with 2.4% of the overall White population of the same age.⁹ Interferon gamma, C-X-C chemokine ligand 10, and IL-22 receptors stimulate the innate immune response, resulting in an overactive danger signaling cascade, which leads to proinflammatory signals against melanocyte antigens.^2,3 The adaptive immune system also participates in the progression of vitiligo by activating dermal dendritic cells to attack melanocytes along with melanocyte-specific cytotoxic T cells.

Immunomodulatory agents utilized in the treatment of metastatic melanoma have been linked to vitiligolike depigmentation. In those receiving PD-1 immunotherapy for metastatic melanoma, vitiligolike lesions have been reported in 15% to 25% of patients.⁶ Typically, the PD-1 molecule has a regulatory function on effector T cells. Interaction of the PD-1 receptor with its ligands occurs primarily in peripheral tissue causing apoptosis and downregulation of effector T cells with the goal of decreasing collateral damage to surrounding tissues by active T cells.⁵ In the tumor microenvironment, however, suppression of the host’s immune response is enhanced by aberrant stimulation of the PD-1 receptor, causing downregulation of the T-cell effector function, T-cell destruction, and apoptosis, which results in continued tumor growth. Nivolumab, a fully humanized monoclonal IgG4 antibody, selectively inhibits the PD-1 receptor, disrupting the regulator pathway that would typically end in T-cell destruction.⁵ Accordingly, the population of active T cells is increased along with the antitumor response.^4,10 Nivolumab exhibits success as an immunotherapeutic agent, with an overall survival rate in patients with metastatic melanoma undergoing nivolumab therapy of 41% to 42% at 3 years and 35% at 5 years.¹¹ However, therapeutic manipulation of the host’s immune response does not come without a cost. Vitiligolike lesions have been reported in up to a quarter of patients receiving PD-1 immunotherapy for metastatic melanoma.⁶

 

The relationship between vitiligolike depigmentation and melanoma can be explained by the immune activation against antigens associated with melanoma that also are expressed by normal melanocytes. In clinical observations of patients with melanoma and patients with vitiligo, antibodies to human melanocyte antigens were present in 80% (24/30) of patients vs 7% (2/28) in the control group.¹² The autoimmune response results from a cross-reaction of melanoma cells that share the same antigens as normal melanocytes, such as melanoma antigen recognized by T cells 1 (MART-1), gp100, and tyrosinase.^13,14

Development of vitiligolike depigmentation in patients with metastatic melanoma treated with nivolumab has been reported to occur between 2 and 15 months after the start of PD-1 therapy. This side effect of treatment correlates with favorable clinical outcomes.^15,16 Enhancing immune recognition of melanocytes in patients with melanoma confers a survival advantage, as studies by Koh et al¹⁷ and Norlund et al¹⁸ involving patients who developed vitiligolike hypopigmentation associated with malignant melanoma indicated a better prognosis than for those without hypopigmentation. The 5-year survival rate of patients with both malignant melanoma and vitiligo was reported as 60% to 67% when it was estimated that only 30% to 50% of patients should have survived that duration of time.^17,18 Similarly, a systematic review of patients with melanoma stages III and IV reported that those with associated hypopigmentation had a 2- to 4-fold decreased risk of disease progression and death compared to patients without depigmentation.⁷

Use of traditional treatment therapies for vitiligo is based on the ability of the therapy to suppress the immune system. However, in patients with metastatic melanoma undergoing immune-modulating cancer therapies, traditional treatment options may counter the antitumor effects of the targeted immunotherapies and should be used with caution. Our patient displayed improvement in the appearance of her starkly contrasting hypopigmented patches with the use of hydroquinone cream 4%, which induced necrotic death of melanocytes by inhibiting the conversion of L-3,4-dihydroxyphenylalanine to melanin by tyrosinase.¹⁹ The effect achieved by using topical hydroquinone 4% was a lighter skin appearance in areas of application.

There is no cure for vitiligo, and although it is a benign condition, it can negatively impact a patient's quality of life. In some countries, vitiligo is confused with leprosy, resulting in a social stigma attached to the diagnosis. Many patients are frightened or embarrassed by the diagnosis of vitiligo and its effects, and they often experience discrimination.² Patients with vitiligo also experience more psychological difficulties such as depression.²⁰ The unpredictability of vitiligo is associated with negative emotions including fear of spreading the lesions, shame, insecurity, and sadness.²¹ Supportive care measures, including psychological support and counseling, are recommended. Additionally, upon initiation of anti–PD-1 therapies, expectations should be discussed with patients concerning the possibilities of depigmentation and associated treatment results. Although the occurrence of vitiligo may cause the patient concern, it should be communicated that its presence is a positive indicator of a vigorous antimelanoma immunity and an increased survival rate.⁷

Vitiligolike depigmentation is a known rare adverse effect of nivolumab treatment. Although aesthetically unfavorable for the patient, the development of vitiligolike lesions while undergoing immunotherapy for melanoma may be a sign of a promising clinical outcome due to an effective immune response to melanoma antigens. Our patient remains in remission without any evidence of melanoma after 9 months of therapy, which offers support for a promising outcome for melanoma patients who experience vitiligolike depigmentation.

To the Editor:

A collision tumor is the coexistence of 2 discrete tumors in the same neoplasm, possibly comprising a malignant tumor and a benign tumor, and thereby complicating appropriate diagnosis and treatment. We present a case of a basal cell carcinoma (BCC) of the scalp that was later found to be in collision with an apocrine hidrocystoma that might have arisen from a nevus sebaceus. Although rare, BCC can coexist with apocrine hidrocystoma. Jayaprakasam and Rene¹ reported a case of a collision tumor containing BCC and hidrocystoma on the eyelid.¹ We present a case of a BCC on the scalp that was later found to be in collision with an apocrine hidrocystoma that possibly arose from a nevus sebaceus.

A 92-year-old Black woman with a biopsy-confirmed primary BCC of the left parietal scalp presented for Mohs micrographic surgery. The pathology report from an outside facility was reviewed. The initial diagnosis had been made with 2 punch biopsies from separate areas of the large nodule—one consistent with nodular and pigmented BCC (Figure 1), and the other revealed nodular ulcerated BCC. Physical examination prior to Mohs surgery revealed a mobile, flesh-colored, 6.2×6.0-cm nodule with minimal overlying hair on the left parietal scalp (Figure 2). During stage-I processing by the histopathology laboratory, large cystic structures were encountered; en face frozen sections showed a cystic tumor. Excised tissue was submitted for permanent processing to aid in diagnosis; the initial diagnostic biopsy slides were requested from the outside facility for review.

The initial diagnostic biopsy slides were reviewed and found to be consistent with nodular and pigmented BCC, as previously reported. Findings from hematoxylin and eosin staining of tissue obtained from Mohs sections were consistent with a combined neoplasm comprising BCC (Figure 3A) and apocrine hidrocystoma (Figure 3B). In addition, one section was characterized by acanthosis, papillomatosis, and sebaceous glands—similar to findings that are seen in a nevus sebaceus (Figure 3C).

The BCC was cleared after stage I; the final wound size was 7×6.6 cm. Although benign apocrine hidrocystoma was still evident at the margin, further excision was not performed at the request of the patient and her family. Partial primary wound closure was performed with pulley sutures. A xenograft was placed over the unclosed central portion. The wound was permitted to heal by second intention.

The clinical differential diagnosis of a scalp nodule includes a pilar cyst, BCC, squamous cell carcinoma, melanoma, cutaneous metastasis, adnexal tumor, atypical fibroxanthoma, and collision tumor. A collision tumor—the association of 2 or more benign or malignant neoplasms—represents a well-known pitfall in making a correct clinical and pathologic diagnosis.² Many theories have been proposed to explain the pathophysiology of collision tumors. Some authors have speculated that they arise from involvement of related cell types.¹ Other theories include induction by cytokines and growth factors secreted from one tumor that provides an ideal environment for proliferation of other cell types, a field cancerization effect of sun-damaged skin, or a coincidence.²

In our case, it is possible that the 2 tumors arose from a nevus sebaceus. One retrospective study of 706 cases of nevus sebaceus (707 specimens) found that 22.5% of cases developed secondary proliferation; of those cases, 18.9% were benign.³ Additionally, in 4.2% of cases of nevus sebaceus, proliferation of 2 or more tumors developed. The most common malignant neoplasm to develop from nevus sebaceus was BCC, followed by squamous cell carcinoma and sebaceous carcinoma. The most common benign neoplasm to develop from nevus sebaceus was trichoblastoma, followed by syringocystadenoma papilliferum.³

Our case highlights the possibility of a sampling error when performing a biopsy of any large neoplasm. Additionally, Mohs surgeons should maintain high clinical suspicion for collision tumors when encountering a large tumor with pathology inconsistent with the original biopsy. Apocrine hidrocystoma should be considered in the differential diagnosis of a large cystic mass of the scalp. Also, it is important to recognize that malignant lesions, such as BCC, can coexist with another benign tumor. Basal cell carcinoma is rare in Black patients, supporting our belief that our patient’s tumors arose from a nevus sebaceus.

It also is important for Mohs surgeons to consider any potential discrepancy between the initial pathology report and Mohs intraoperative pathology that can impact diagnosis, the aggressiveness of the tumors identified, and how such aggressiveness may affect management options.^4,5 Some dermatology practices request biopsy slides from patients who are referred for Mohs micrographic surgery for internal review by a dermatopathologist before surgery is performed; however, this protocol requires additional time and adds costs for the overall health care system.⁴ One study found that internal review of outside biopsy slides resulted in a change in diagnosis in 2.2% of patients (N=3345)—affecting management in 61% of cases in which the diagnosis was changed.⁴ Another study (N=163) found that the reported aggressiveness of 50.5% of nonmelanoma cases in an initial biopsy report was changed during Mohs micrographic surgery.⁵ Mohs surgeons should be aware that discrepancies can occur, and if a discrepancy is discovered, the procedure may be paused until the initial biopsy slide is reviewed and further information is collected.

To the Editor:

A collision tumor is the coexistence of 2 discrete tumors in the same neoplasm, possibly comprising a malignant tumor and a benign tumor, and thereby complicating appropriate diagnosis and treatment. We present a case of a basal cell carcinoma (BCC) of the scalp that was later found to be in collision with an apocrine hidrocystoma that might have arisen from a nevus sebaceus. Although rare, BCC can coexist with apocrine hidrocystoma. Jayaprakasam and Rene¹ reported a case of a collision tumor containing BCC and hidrocystoma on the eyelid.¹ We present a case of a BCC on the scalp that was later found to be in collision with an apocrine hidrocystoma that possibly arose from a nevus sebaceus.

A 92-year-old Black woman with a biopsy-confirmed primary BCC of the left parietal scalp presented for Mohs micrographic surgery. The pathology report from an outside facility was reviewed. The initial diagnosis had been made with 2 punch biopsies from separate areas of the large nodule—one consistent with nodular and pigmented BCC (Figure 1), and the other revealed nodular ulcerated BCC. Physical examination prior to Mohs surgery revealed a mobile, flesh-colored, 6.2×6.0-cm nodule with minimal overlying hair on the left parietal scalp (Figure 2). During stage-I processing by the histopathology laboratory, large cystic structures were encountered; en face frozen sections showed a cystic tumor. Excised tissue was submitted for permanent processing to aid in diagnosis; the initial diagnostic biopsy slides were requested from the outside facility for review.

The initial diagnostic biopsy slides were reviewed and found to be consistent with nodular and pigmented BCC, as previously reported. Findings from hematoxylin and eosin staining of tissue obtained from Mohs sections were consistent with a combined neoplasm comprising BCC (Figure 3A) and apocrine hidrocystoma (Figure 3B). In addition, one section was characterized by acanthosis, papillomatosis, and sebaceous glands—similar to findings that are seen in a nevus sebaceus (Figure 3C).

The BCC was cleared after stage I; the final wound size was 7×6.6 cm. Although benign apocrine hidrocystoma was still evident at the margin, further excision was not performed at the request of the patient and her family. Partial primary wound closure was performed with pulley sutures. A xenograft was placed over the unclosed central portion. The wound was permitted to heal by second intention.

The clinical differential diagnosis of a scalp nodule includes a pilar cyst, BCC, squamous cell carcinoma, melanoma, cutaneous metastasis, adnexal tumor, atypical fibroxanthoma, and collision tumor. A collision tumor—the association of 2 or more benign or malignant neoplasms—represents a well-known pitfall in making a correct clinical and pathologic diagnosis.² Many theories have been proposed to explain the pathophysiology of collision tumors. Some authors have speculated that they arise from involvement of related cell types.¹ Other theories include induction by cytokines and growth factors secreted from one tumor that provides an ideal environment for proliferation of other cell types, a field cancerization effect of sun-damaged skin, or a coincidence.²

In our case, it is possible that the 2 tumors arose from a nevus sebaceus. One retrospective study of 706 cases of nevus sebaceus (707 specimens) found that 22.5% of cases developed secondary proliferation; of those cases, 18.9% were benign.³ Additionally, in 4.2% of cases of nevus sebaceus, proliferation of 2 or more tumors developed. The most common malignant neoplasm to develop from nevus sebaceus was BCC, followed by squamous cell carcinoma and sebaceous carcinoma. The most common benign neoplasm to develop from nevus sebaceus was trichoblastoma, followed by syringocystadenoma papilliferum.³

Our case highlights the possibility of a sampling error when performing a biopsy of any large neoplasm. Additionally, Mohs surgeons should maintain high clinical suspicion for collision tumors when encountering a large tumor with pathology inconsistent with the original biopsy. Apocrine hidrocystoma should be considered in the differential diagnosis of a large cystic mass of the scalp. Also, it is important to recognize that malignant lesions, such as BCC, can coexist with another benign tumor. Basal cell carcinoma is rare in Black patients, supporting our belief that our patient’s tumors arose from a nevus sebaceus.

It also is important for Mohs surgeons to consider any potential discrepancy between the initial pathology report and Mohs intraoperative pathology that can impact diagnosis, the aggressiveness of the tumors identified, and how such aggressiveness may affect management options.^4,5 Some dermatology practices request biopsy slides from patients who are referred for Mohs micrographic surgery for internal review by a dermatopathologist before surgery is performed; however, this protocol requires additional time and adds costs for the overall health care system.⁴ One study found that internal review of outside biopsy slides resulted in a change in diagnosis in 2.2% of patients (N=3345)—affecting management in 61% of cases in which the diagnosis was changed.⁴ Another study (N=163) found that the reported aggressiveness of 50.5% of nonmelanoma cases in an initial biopsy report was changed during Mohs micrographic surgery.⁵ Mohs surgeons should be aware that discrepancies can occur, and if a discrepancy is discovered, the procedure may be paused until the initial biopsy slide is reviewed and further information is collected.

To the Editor:

A collision tumor is the coexistence of 2 discrete tumors in the same neoplasm, possibly comprising a malignant tumor and a benign tumor, and thereby complicating appropriate diagnosis and treatment. We present a case of a basal cell carcinoma (BCC) of the scalp that was later found to be in collision with an apocrine hidrocystoma that might have arisen from a nevus sebaceus. Although rare, BCC can coexist with apocrine hidrocystoma. Jayaprakasam and Rene¹ reported a case of a collision tumor containing BCC and hidrocystoma on the eyelid.¹ We present a case of a BCC on the scalp that was later found to be in collision with an apocrine hidrocystoma that possibly arose from a nevus sebaceus.

A 92-year-old Black woman with a biopsy-confirmed primary BCC of the left parietal scalp presented for Mohs micrographic surgery. The pathology report from an outside facility was reviewed. The initial diagnosis had been made with 2 punch biopsies from separate areas of the large nodule—one consistent with nodular and pigmented BCC (Figure 1), and the other revealed nodular ulcerated BCC. Physical examination prior to Mohs surgery revealed a mobile, flesh-colored, 6.2×6.0-cm nodule with minimal overlying hair on the left parietal scalp (Figure 2). During stage-I processing by the histopathology laboratory, large cystic structures were encountered; en face frozen sections showed a cystic tumor. Excised tissue was submitted for permanent processing to aid in diagnosis; the initial diagnostic biopsy slides were requested from the outside facility for review.

The initial diagnostic biopsy slides were reviewed and found to be consistent with nodular and pigmented BCC, as previously reported. Findings from hematoxylin and eosin staining of tissue obtained from Mohs sections were consistent with a combined neoplasm comprising BCC (Figure 3A) and apocrine hidrocystoma (Figure 3B). In addition, one section was characterized by acanthosis, papillomatosis, and sebaceous glands—similar to findings that are seen in a nevus sebaceus (Figure 3C).

The BCC was cleared after stage I; the final wound size was 7×6.6 cm. Although benign apocrine hidrocystoma was still evident at the margin, further excision was not performed at the request of the patient and her family. Partial primary wound closure was performed with pulley sutures. A xenograft was placed over the unclosed central portion. The wound was permitted to heal by second intention.

The clinical differential diagnosis of a scalp nodule includes a pilar cyst, BCC, squamous cell carcinoma, melanoma, cutaneous metastasis, adnexal tumor, atypical fibroxanthoma, and collision tumor. A collision tumor—the association of 2 or more benign or malignant neoplasms—represents a well-known pitfall in making a correct clinical and pathologic diagnosis.² Many theories have been proposed to explain the pathophysiology of collision tumors. Some authors have speculated that they arise from involvement of related cell types.¹ Other theories include induction by cytokines and growth factors secreted from one tumor that provides an ideal environment for proliferation of other cell types, a field cancerization effect of sun-damaged skin, or a coincidence.²

In our case, it is possible that the 2 tumors arose from a nevus sebaceus. One retrospective study of 706 cases of nevus sebaceus (707 specimens) found that 22.5% of cases developed secondary proliferation; of those cases, 18.9% were benign.³ Additionally, in 4.2% of cases of nevus sebaceus, proliferation of 2 or more tumors developed. The most common malignant neoplasm to develop from nevus sebaceus was BCC, followed by squamous cell carcinoma and sebaceous carcinoma. The most common benign neoplasm to develop from nevus sebaceus was trichoblastoma, followed by syringocystadenoma papilliferum.³

Our case highlights the possibility of a sampling error when performing a biopsy of any large neoplasm. Additionally, Mohs surgeons should maintain high clinical suspicion for collision tumors when encountering a large tumor with pathology inconsistent with the original biopsy. Apocrine hidrocystoma should be considered in the differential diagnosis of a large cystic mass of the scalp. Also, it is important to recognize that malignant lesions, such as BCC, can coexist with another benign tumor. Basal cell carcinoma is rare in Black patients, supporting our belief that our patient’s tumors arose from a nevus sebaceus.

It also is important for Mohs surgeons to consider any potential discrepancy between the initial pathology report and Mohs intraoperative pathology that can impact diagnosis, the aggressiveness of the tumors identified, and how such aggressiveness may affect management options.^4,5 Some dermatology practices request biopsy slides from patients who are referred for Mohs micrographic surgery for internal review by a dermatopathologist before surgery is performed; however, this protocol requires additional time and adds costs for the overall health care system.⁴ One study found that internal review of outside biopsy slides resulted in a change in diagnosis in 2.2% of patients (N=3345)—affecting management in 61% of cases in which the diagnosis was changed.⁴ Another study (N=163) found that the reported aggressiveness of 50.5% of nonmelanoma cases in an initial biopsy report was changed during Mohs micrographic surgery.⁵ Mohs surgeons should be aware that discrepancies can occur, and if a discrepancy is discovered, the procedure may be paused until the initial biopsy slide is reviewed and further information is collected.

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

 

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

 

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

To the Editor:

Subcutaneous panniculitic T-cell lymphoma (SPTCL) is a rare cutaneous T-cell lymphoma that was first described in 1991¹ and comprises less than 1% of all non-Hodgkin lymphomas (NHLs). It most commonly occurs in young adults, with a median patient age of 36 years and a slight female predominance.² Patients typically present with skin nodules or deep-seated plaques involving the legs, arms, and/or trunk. Presentation on the face is less common.^2,3 Paraneoplastic edema has been reported in several cases of SPTCL with facial and periorbital swelling.^4-9

Diagnosis of SPTCL is achieved via analysis of a deep tissue skin biopsy and close clinicopathologic correlation. Histopathology demonstrates lobular panniculitis with an atypical lymphoid infiltrate in the subcutaneous tissue with predominantly CD8⁺ T cells without overlying epidermotropism or interface dermatitis.³ The degree of cellular atypia, fat necrosis, karyorrhexis, cytophagia, and lack of angioinvasion can help to distinguish SPTCL from other panniculitides.^2,3

The prognosis of SPTCL is good, with a 5-year survival rate of 82%, and many patients are able to achieve remission.² However, SPTCL can progress to a fatal hemophagocytic syndrome, which has been reported in 17% of cases, making early diagnosis and treatment of this malignancy imperative.^1,2 Treatment varies depending on the progression and extent of disease and can include the use of steroids, multidrug chemotherapy regimens, radiotherapy, and stem cell transplant in refractory cases.^2-4,10,11

Subcutaneous panniculitic T-cell lymphoma with edema has been reported in a 2-year-old child.¹² We present a case of SPTCL in an adult patient with known stage IV chronic lymphocytic leukemia (CLL) who also had full-body edema.

A 60-year-old woman with a 7-year history of stage IV CLL presented with anasarca of 3 months’ duration. At the time of presentation to dermatology, physical examination revealed erythematous tender nodules on the arms and legs. She had no other medical conditions and was undergoing treatment with ibrutinib for the CLL. The patient reported profound fatigue but no fever, chills, night sweats, cough, or dyspnea. The swelling had begun initially in the legs and progressively worsened to involve the arms, face, and body. She was hospitalized and treated with intravenous steroids and antihistamines, which led to minor improvement in the swelling. The patient’s preliminary diagnosis of erythema nodosum was thought to be related to the CLL or ibrutinib; therefore, treatment subsequently was discontinued and she was discharged from the hospital.

The swelling continued to worsen over the following 3 months, and the patient gained approximately 25 pounds. She presented to our office again with severe periorbital, facial, and lip edema as well as diffuse edema of the torso, arms, and legs (Figure 1). Erythematous tender subcutaneous nodules were noted on the right proximal thigh, left lateral calf, and forearms. She was again hospitalized, and extensive evaluation was performed to exclude other causes of anasarca, including a complete blood cell count; comprehensive metabolic profile; hepatitis panels; HIV test; C3 and C4, complement CH50, C1 esterase inhibitor, IgE, and angiotensin-converting enzyme levels; urine protein to creatinine ratio; computed tomography of the chest, abdomen, and pelvis; and allergy evaluation. The analyses failed to reveal the cause of the anasarca.

During hospitalization, the patient underwent a lymph node biopsy, bone marrow biopsy, and a 6-mm punch biopsy of the right thigh nodule. The lymph node and bone marrow biopsy results were consistent with the known diagnosis of CLL, and the patient was started on intravenous chemotherapy with bendamustine. The skin biopsy demonstrated a predominant T-cell infiltrate consistent with a lobular panniculitis with variable amounts of adipocytes rimmed by lymphocytes, nuclear debris, and karyorrhexis (Figure 2). CD3⁺, CD8⁺, and CD4⁻ T cells were positive for T-cell receptor (TCR) βF1 and negative for TCR-γ with strong expression of cytotoxic markers including granzyme B, perforin, and T-cell intracytoplasmic antigen 1. Rare CD56⁺ cells also were noted. The biopsy did not demonstrate any notable interface dermatitis, epidermotropism, or angioinvasion. T-cell receptor gene rearrangement studies did not show clonality for γ- or β-chain probes. Subcutaneous panniculitic T-cell lymphoma was diagnosed, making this case unique with the presentation of anasarca. This case also is noteworthy due to the rare diagnosis of the secondary malignancy of SPTCL in a patient with known CLL. The patient opted to pursue hospice and comfort measures due to the effects of persistent pancytopenia and the progression of CLL. She died 2 months later.

 

Clinical courses of SPTCL vary based on the TCR phenotype and immunophenotypic characteristics of the tumor cells. The TCR-αβ phenotype, as described in this case, typically is CD4⁻, CD8⁺, and CD56^– and leads to a more indolent disease course. Lymphomas with the TCR-γδ phenotype typically are CD4⁻, CD8⁻, and CD56⁺; they often are associated with hemophagocytic syndrome and thus a worse prognosis. In 2009, the World Health Organization–European Organization for Research and Treatment of Cancer classification of primary cutaneous lymphomas restricted the category of SPTCL to the TCR-αβ phenotype due to the stark differences between the 2 types. The TCR-γδ phenotype was given its own diagnostic category—primary cutaneous γδ T-cell lymphoma.³

Patients with SPTCL commonly present with nodular skin lesions or deep-seated plaques on the legs, arms, and/or trunk; presentation on the face is rare.^2,3 Fever, chills, night sweats, and/or weight loss were present in approximately 50% of recorded cases. Underlying autoimmune disease was present in 12 of 63 (19%) patients in a 2008 study.² Facial and periorbital swelling with SPTCL has been reported.^4-9 The presentation of anasarca, as seen in our adult patient, has been reported in a 2-year-old child.¹² Anasarca as a presenting symptom of NHL is a rare phenomenon proposed to be induced by malignant cells secreting a cytokine that causes a vascular leak syndrome.¹³ Specifically, tumor necrosis factor α was found to be elevated in at least 2 patients with NHL presenting with anasarca in a prior study. Tumor necrosis factor α is known to cause increased capillary permeability, vascular leakage, and development of edema.¹³ In retrospect, obtaining cytokine levels in our patient would have been useful to support or refute tumor necrosis factor α as a possible cause of anasarca in the setting of NHL. This case continues to highlight that a diagnosis of SPTCL and analysis of a skin biopsy should be considered in cases of sudden unremitting facial and/or body swelling that cannot be explained by other more common causes.

Subcutaneous panniculitic T-cell lymphoma can be diagnosed and distinguished from other panniculitides via analysis of a deep tissue skin biopsy. Multiple biopsies may be required to ensure an adequate sample is obtained.⁴ Histopathology displays an atypical lymphoid infiltrate with a predominant presence of T cells. Neoplastic cells show CD3⁺, CD8⁺, and CD4⁻ T cells, which strongly express cytotoxic proteins such as granzyme B, T-cell intracellular antigen 1, and perforin.³ The degree of cellular atypia, fat necrosis, karyorrhexis, and cytophagia, as well as the lack of angioinvasion, interface dermatitis, and epidermotropism help to distinguish SPTCL from other panniculitides.^2,3 According to a previous study, clonal TCR gene rearrangement was identified in 50% to 80% of cases, but the absence of this clonal rearrangement does not exclude the diagnosis.¹⁴

This case also highlights the occurrence of secondary malignancies in patients with CLL, an NHL that is classified as a low-grade lymphoproliferative malignancy with clonal expansion of B cells.¹⁵ Secondary CTCLs in patients with CLL are rare, but they have been previously described. In 2017, Chang et al¹⁶ identified 12 patients with CLL who subsequently developed CTCL between 1992 and 2008. Of the 12 patients, 7 developed mycosis fungoides, 3 had CTCL not otherwise specified, 1 had mature T-cell lymphoma not otherwise specified, and 1 had primary cutaneous CD30⁺ T-cell lymphoma.¹⁶ The proliferation of 2 separate lymphocytic lineages is rare, but this study demonstrated an increased risk for CTCL to develop in patients with CLL. One possible explanation is that malignant cells come from a common stem cell progenitor or from genetic events. They occur secondary to carcinogens, viruses, or cytokines from T-cell or B-cell clones; they evolve due to treatment of the preexisting lymphoproliferative disease; or they occur simply by coincidence. The behavior of the CTCL may be more aggressive in patients with CLL due to immunosuppression, which may have contributed to the extreme presentation in our patient.¹⁶ Subcutaneous panniculitic T-cell lymphoma also has been reported in a patient with CLL that was thought to be associated with prior rituximab treatment.¹⁷

Treatment of SPTCL depends on the severity and course of the disease. In patients with more indolent disease, systemic steroids have been the most frequently used initial treatment.^2,3,10 However, the disease often will progress after steroid tapering and require further intervention. Localized lesions may be treated with radiation alone or in combination with other systemic therapies.^3,10 In refractory, aggressive, or relapsing cases, polychemotherapeutic regimens have proven to produce long-term remission in 30% of patients, with an overall response rate of 50%.¹⁰ These regimens most commonly have included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like treatment (EPOCH regimen [etoposide, prednisone, oncovin, cyclophosphamide, and doxorubicin hydrochloride]).^3,10 A stem cell transplant can be considered in patients with recurrent and refractory disease, and it also has been shown to induce remission.^4,17 In patients with a good response to therapy, the disease often can be controlled for long periods of time, with an estimated 5-year survival rate of 80%.¹⁵

This case highlights the diagnostic challenges and variable presentations of SPTCL. Dermatologists, oncologists, and dermatopathologists should be aware of this condition and consider it in the differential diagnosis of a patient with a hematologic malignancy and unremitting facial and/or body swelling without any other cause. The possibility of a secondary hematologic cancer in a patient with CLL also must be taken into consideration. Early diagnosis and treatment can minimize morbidity and induce remission in most patients.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

 

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

 

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.

To the Editor:

The organisms of the genus Nocardia are gram-positive, ubiquitous, aerobic actinomycetes found worldwide in soil, decaying organic material, and water.¹ The genus Nocardia includes more than 50 species; some species, such as Nocardia asteroides, Nocardia farcinica, Nocardia nova, and Nocardia brasiliensis, are the cause of nocardiosis in humans and animals.^2,3 Nocardiosis is a rare and opportunistic infection that predominantly affects immunocompromised individuals; however, up to 30% of infections can occur in immunocompetent hosts.⁴ Nocardiosis can manifest in 3 disease forms: cutaneous, pulmonary, or disseminated. Cutaneous nocardiosis commonly develops in immunocompetent individuals who have experienced a predisposing traumatic injury to the skin,⁵ and it can exhibit a diverse variety of clinical manifestations, making diagnosis difficult. We describe a case of serious progressive primary cutaneous nocardiosis with an unusual presentation in an immunocompetent patient.

A 26-year-old immunocompetent man presented with pain, swelling, nodules, abscesses, ulcers, and sinus drainage of the left arm. The left elbow lesion initially developed at the site of a trauma 6 years prior that was painless but was contaminated with mossy soil. The condition slowly progressed over the next 2 years, and the patient experienced increased swelling and eventually developed multiple draining sinus tracts. Over the next 4 years, the lesions multiplied, spreading to the forearm and upper arm; associated severe pain and swelling at the elbow and wrist joint developed. The patient sought medical care at a local hospital and subsequently was diagnosed with suspected cutaneous tuberculosis. The patient was empirically treated with a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol; however, the lesions continued to progress and worsen. The patient had to stop antibiotic treatment because of substantially elevated alanine aminotransferase and aspartate aminotransferase levels.

He subsequently was evaluated at our hospital. He had no notable medical history and was afebrile. Physical examination revealed multiple erythematous nodules, abscesses, and ulcers on the left arm. There were several nodules with open sinus tracts and seropurulent crusts along with numerous atrophic, ovoid, stellate scars. Other nodules and ulcers with purulent drainage were located along the lymphatic nodes extending up the patient’s left forearm (Figure 1A). The yellowish-white pus discharge from several active sinuses contained no apparent granules. The lesions were densely distributed along the elbow, wrist, and shoulder, which resulted in associated skin swelling and restricted joint movement. The left axillary lymph nodes were enlarged.

Laboratory analyses revealed a hemoglobin level of 9.6 g/dL (reference range, 13–17.5 g/dL), platelet count of 621×10⁹/L (reference range, 125–350×10⁹/L), and leukocyte count of 14.3×10⁹/L (reference range, 3.5–9.5 ×10⁹/L). C-reactive protein level was 88.4 mg/L (reference range, 0–10 mg/L). Blood, renal, and liver tests, as well as tumor marker, peripheral blood lymphocyte subset, immunoglobulin, and complement results were within reference ranges. Results for Treponema pallidum and HIV antibody tests were negative. Hepatitis B virus markers were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody, and the serum concentration of hepatitis B virus DNA was 3.12×10⁷ IU/mL (reference range, <5×10² IU/mL). Computed tomography of the chest and cranium were unremarkable. Ultrasonography of the left arm revealed multiple vertical sinus tracts and several horizontal communicating branches that were accompanied by worm-eaten bone destruction (Figure 2).

Additional testing included histopathologic staining of a skin tissue specimen—hematoxylin and eosin, periodic acid–Schiff, and acid-fast staining—showed nonspecific, diffuse, inflammatory cell infiltration suggestive of chronic suppurative granuloma (Figure 3) but failed to reveal any special strains or organisms. Gram stain examination of the purulent fluid collected from the subcutaneous tissue showed no apparent positive bacillus or filamentous granules. The specimen was then inoculated on Sabouraud dextrose agar and Lowenstein-Jensen medium for fungus and mycobacteria culture, respectively. After 5 days, chalky, yellow, adherent colonies were observed on the Löwenstein-Jensen medium, and after 26 days, yellow crinkled colonies were observed on Sabouraud dextrose agar. The colonies were then inoculated on Columbia blood agar and incubated for 1 week to aid in the identification of organisms. Growth of yellow colonies that were adherent to the agar, moist, and smooth with a velvety surface, as well as a characteristic moldy odor resulted. Gram staining revealed gram-positive, thin, and beaded branching filaments (Figure 4). Based on colony characteristics, physiological properties, and biochemical tests, the isolate was identified as Nocardia. Results of further investigations employing polymerase chain reaction analysis of the skin specimen and bacterial colonies using a Nocardia genus 596-bp fragment of 16S ribosomal RNA primer (forward primer NG1: 5’-ACCGACCACAAGGGG-3’, reverse primer NG2: 5’-GGTTGTAACCTCTTCGA-3’)⁶ were completely consistent with the reference for identification of N brasiliensis. Evaluation of these results led to a diagnosis of cutaneous nocardiosis after traumatic inoculation.

Because there was a high suspicion of actinophytosis or nocardiosis at admission, the patient received a combination antibiotic treatment with intravenous aqueous penicillin (4 million U every 4 hours) and oral trimethoprim-sulfamethoxazole (160/800 mg twice daily). Subsequently, treatment was changed to a combination of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily) and moxifloxacin (400 mg once daily) based on pathogen identification and antibiotic sensitivity testing. After 1 month of treatment, the cutaneous lesions and left limb swelling dramatically improved and purulent drainage ceased, though some scarring occurred during the healing process. In addition, the mobility of the affected shoulder, elbow, and wrist joints slightly improved. Notable improvement in the mobility and swelling of the joints was observed at 6-month follow-up (Figure 1B). The patient continues to be monitored on an outpatient basis.

Cutaneous nocardiosis is a disfiguring granulomatous infection involving cutaneous and subcutaneous tissue that can progress to cause injury to viscera and bone.⁷ It has been called one of the great imitators because cutaneous nocardiosis can present in multiple forms,^8,9 including mycetoma, sporotrichoid infection, superficial skin infection, and disseminated infection with cutaneous involvement. The differential diagnoses of cutaneous nocardiosis are broad and include tuberculosis; actinomycosis; deep fungal infections such as sporotrichosis, blastomycosis, phaeohyphomycosis, histoplasmosis, and coccidioidomycosis; other bacterial causes of cellulitis, abscess, or ecthyma; and malignancies.¹⁰ The principle method of diagnosis is the identification of Nocardia from the infection site.

 

Our patient ultimately was diagnosed with primary cutaneous nocardiosis resulting from a traumatic injury to the skin that was contaminated with soil. The clinical manifestation pattern was a compound type, including both mycetoma and sporotrichoid infections. Initially, Nocardia mycetoma occurred with subcutaneous infection by direct extension^10,11 and appeared as dense, predominantly painless, swollen lesions. After 4 years, the skin lesions continued to spread linearly to the patient’s upper arm and forearm and manifested as the sporotrichoid infection type with painful swollen lesions at the site of inoculation and painful enlargement of the ipsilateral axillary lymph node.

Although nocardiosis is found worldwide, it is endemic to tropical and subtropical regions such as India, Africa, Southeast Asia, and Latin America.¹² Nocardiosis most often is observed in individuals aged 20 to 40 years. It affects men more than women, and it commonly occurs in field laborers and cultivators whose occupations involve direct contact with the soil.¹³ Most lesions are found on the lower extremities, though localized nocardiosis infections can occur in other areas such as the neck, breasts, back, buttocks, and elbows.

Our patient initially was misdiagnosed, and treatment was delayed for several reasons. First, nocardiosis is not common in China, and most clinicians are unfamiliar with the disease. Second, the related lesions do not have specific features, and our patient had a complex clinical presentation that included mycetoma and sporotrichoid infection. Third, the characteristic grain of Nocardia species is small but that of N brasiliensis is even smaller (approximately 0.1–0.2 mm in diameter), which makes visualization difficult in both histopathologic and microbiologic examinations.¹⁴ The histopathologic examination results of our patient in the local hospital were nonspecific. Fourth, our patient did not initially go to the hospital but instead purchased some over-the-counter antibiotic ointments for external application because the lesions were painless. Moreover, microbiologic smear and culture examinations were not conducted in the local hospital before administering antituberculosis treatment to the patient. Instead, a polymerase chain reaction examination of skin lesion tissue for tubercle bacilli and atypical mycobacteria was negative. These findings imply that the traditional microbial smear and culture evaluations cannot be omitted. Furthermore, culture examinations should be conducted on multiple skin tissue and purulent fluid specimens to increase the likelihood of detection. These cultures should be monitored for at least 2 to 4 weeks because Nocardia is a slow-growing organism.¹⁰

The optimal antimicrobial treatment regimens for nocardiosis have not been firmly established.¹⁵ Trimethoprim-sulfamethoxazole is regarded as the first-line antimicrobial agent for treatment of nocardial infections. The optimal duration of antimicrobial therapy for nocardiosis also has not been determined, and the treatment regimen depends on the severity and extent of the infection as well as on the presence of infection-related complications. The main complication is bone involvement. Notable bony changes include periosteal thickening, osteoporosis, and osteolysis.

We considered the severity of skin lesions and bone marrow invasion in our patient and planned to treat him continually with oral trimethoprim-sulfamethoxazole according to the in vitro drug susceptibility test. The patient showed clinical improvement after 1 month of treatment, and he continued to improve after 6 months of treatment. To prevent recurrence, we found it necessary to treat the patient with a long-term antibiotic course over 6 to 12 months.¹⁶

Cutaneous nocardiosis remains a diagnostic challenge because of its nonspecific and diverse clinical and histopathological presentations. Diagnosis is further complicated by the inherent difficulty of cultivating and identifying the clinical isolate in the laboratory. A high degree of clinical suspicion followed by successful identification of the organism by a laboratory technologist will aid in the early diagnosis and treatment of the infection, ultimately reducing the risk for complications and morbidity.

To the Editor:

An 85-year-old man with a history of hypertension and chronic kidney disease presented with a localized darkening patch of hair on the left parietal scalp that had progressed over the last 7 years (Figure 1A). He had no prior history of skin cancer. Physical examination revealed the remainder of the hair was gray. There was an irregularly pigmented plaque on the skin underlying the darkened hair measuring 5.0 cm in diameter that was confirmed to be melanoma (Figure 1B). He underwent a staged excision to remove the lesion. The surgical defect was closed via a 5.0×6.0-cm full-thickness skin graft. 

The initial biopsy showed melanoma in situ. However, the final pathology report following the excision revealed an invasive melanoma with a Breslow depth of 1.0 mm (Clark level IV; American Joint Committee on Cancer T1b).¹ Histopathology showed pigment deposition with surrounding deep follicular extension of melanoma (Figure 2).

The patient declined a sentinel lymph node biopsy and agreed to a genetic profile assessment.² The results of the test identified the patient had a low probability of a positive sentinel lymph node and the lowest risk of melanoma recurrence within 5 years. The patient was clear of disease at 12-month follow-up.

Based on a PubMed search of articles indexed for MEDLINE using the terms hair repigmentation and melanoma, there have been 11 other reported cases of hair repigmentation associated with melanoma (Table).^3-13 It initially was suspected that this rare phenomenon primarily existed in the female population, as the first 5 cases were reported solely in females,^3-7 possibly due to the prevalence of androgenetic alopecia in males.¹¹ However, 6 cases of repigmentation associated with melanoma were later reported in males^8-13; our patient represents an additional reported case in a male. It is unknown if there is a higher prevalence of this phenomenon among males or females.

Most previously reported cases of repigmentation were associated with melanoma in situ, lentigo maligna type. Repigmentation also has been reported in malignant melanoma, as documented in our patient, as well as desmoplastic and amelanotic melanoma.^5,6 In every case, the color of the repigmentation was darker than the rest of the patient’s hair; however, the repigmentation color can be different from the patient’s original hair color from their youth.^4,5,11

The exact mechanism responsible for hair repigmentation in the setting of melanoma is unclear. It has been speculated from prior cases that repigmentation may be caused by paracrine stimulation from melanoma cells activating adjacent benign hair follicle melanocytes to produce melanin.^7,14,15 This process likely is due to cytokines or growth factors, such as c-kit ligand.^14,15 Several neural and immune networks and mediators activate the receptor tyrosine kinase KIT, which is thought to play a role in activating melanogenesis within the hair bulb.¹⁴ These signals also could originate from changes in the microenvironment instead of the melanoma cells themselves.⁶ Another possible mechanism is that repigmentation was caused by melanin-producing malignant melanocytes.⁴

Because this phenomenon typically occurs in older patients, the cause of repigmentation also could be related to chronic sun damage, which may result in upregulation of stem cell factor and α-melanocyte–stimulating hormone, as well as other molecules associated with melanogenesis, such as c-KIT receptor and tyrosinase.^15,16 Upregulation of these molecules can lead to an increased number of melanocytes within the hair bulb. In addition, UVA and narrowband UVB have been recognized as major players in melanocyte stimulation. Phototherapy with UVA or narrowband UVB has been used for repigmentation in vitiligo patients.¹⁷

 

In cases without invasion of hair follicles by malignant cells, repigmentation more likely results from external signals stimulating benign bulbar melanocytes to produce melanin rather than melanoma cell growth extending into the hair bulb.⁶ In these cases, there is an increase in the number of hair bulbar melanocytes with a lack of malignant morphology in the hair bulb.⁸ If the signals are directly from melanoma cells in the hair bulb, it is unknown how the malignant cells upregulated melanogenesis in adjacent benign melanocytes or which specific signals required for normal pigmentation were involved in these repigmentation cases.⁶

Use of medications was ruled out as an underlying cause of the repigmentation in our patient. Drug-related repigmentation of the hair typically is observed in a diffuse generalized pattern. In our case, the repigmentation was localized to the area of the underlying dark patch, and the patient was not on any medications that could cause hair hyperpigmentation. Hyperpigmentation has been associated with acitretin, lenalidomide, corticosteroids, erlotinib, latanoprost, verapamil, tamoxifen, levodopa, thalidomide, PD-1 inhibitors, and tumor necrosis α inhibitors.^18-30 Repigmentation also has been reported after local radiotherapy and herpes zoster infection.^31,32

The underlying melanoma in our patient was removed by staged square excision. Excision was the treatment of choice for most similar reported cases. Radiotherapy was utilized in two different cases.^3,4 In one case, radiotherapy was successfully used to treat melanoma in situ, lentigo maligna type; the patient’s hair grew back to its original color, which suggests that normal hair physiology was restored once melanoma cells were eliminated.³ One reported case demonstrated successful treatment of lentigo maligna type–melanoma with imiquimod cream 5% applied 6 times weekly for 9 months with a positive cosmetic result.⁹ The exact mechanism of imiquimod is not fully understood. Imiquimod induces cytokines to stimulate the production of IFN-α via activation of toll-like receptor 7.³³ There was complete clearing of the lesion as well as the hair pigmentation,⁹ which suggests that the treatment also eliminated deeper cells influencing pigmentation. A case of malignant amelanotic melanoma was successfully treated with anti–PD-1 antibody pembrolizumab (2 mg/kg every 3 weeks), with no recurrence at 12 months. Pembrolizumab acts as an immune checkpoint inhibitor by binding to the PD-1 receptor and allowing the immune system to recognize and attack melanoma cells. After 5 doses of pembrolizumab, the patient was clear of disease and his hair color returned to gray.⁵

In 2022, melanoma was estimated to be the fifth most commonly diagnosed cancer among men and women in the United States.³⁴ Early melanoma detection is a critical factor in achieving positive patient outcomes. Hair repigmentation is a potentially serious phenomenon that warrants a physician visit. Melanoma lesions under the hair may be overlooked because of limited visibility. Physicians must inspect spontaneous hair repigmentation with high suspicion and interpret the change as a possible indirect result of melanoma. Overall, it is important to increase public awareness of regular skin checks and melanoma warning signs.

To the Editor:

An 85-year-old man with a history of hypertension and chronic kidney disease presented with a localized darkening patch of hair on the left parietal scalp that had progressed over the last 7 years (Figure 1A). He had no prior history of skin cancer. Physical examination revealed the remainder of the hair was gray. There was an irregularly pigmented plaque on the skin underlying the darkened hair measuring 5.0 cm in diameter that was confirmed to be melanoma (Figure 1B). He underwent a staged excision to remove the lesion. The surgical defect was closed via a 5.0×6.0-cm full-thickness skin graft. 

The initial biopsy showed melanoma in situ. However, the final pathology report following the excision revealed an invasive melanoma with a Breslow depth of 1.0 mm (Clark level IV; American Joint Committee on Cancer T1b).¹ Histopathology showed pigment deposition with surrounding deep follicular extension of melanoma (Figure 2).

The patient declined a sentinel lymph node biopsy and agreed to a genetic profile assessment.² The results of the test identified the patient had a low probability of a positive sentinel lymph node and the lowest risk of melanoma recurrence within 5 years. The patient was clear of disease at 12-month follow-up.

Based on a PubMed search of articles indexed for MEDLINE using the terms hair repigmentation and melanoma, there have been 11 other reported cases of hair repigmentation associated with melanoma (Table).^3-13 It initially was suspected that this rare phenomenon primarily existed in the female population, as the first 5 cases were reported solely in females,^3-7 possibly due to the prevalence of androgenetic alopecia in males.¹¹ However, 6 cases of repigmentation associated with melanoma were later reported in males^8-13; our patient represents an additional reported case in a male. It is unknown if there is a higher prevalence of this phenomenon among males or females.

Most previously reported cases of repigmentation were associated with melanoma in situ, lentigo maligna type. Repigmentation also has been reported in malignant melanoma, as documented in our patient, as well as desmoplastic and amelanotic melanoma.^5,6 In every case, the color of the repigmentation was darker than the rest of the patient’s hair; however, the repigmentation color can be different from the patient’s original hair color from their youth.^4,5,11

The exact mechanism responsible for hair repigmentation in the setting of melanoma is unclear. It has been speculated from prior cases that repigmentation may be caused by paracrine stimulation from melanoma cells activating adjacent benign hair follicle melanocytes to produce melanin.^7,14,15 This process likely is due to cytokines or growth factors, such as c-kit ligand.^14,15 Several neural and immune networks and mediators activate the receptor tyrosine kinase KIT, which is thought to play a role in activating melanogenesis within the hair bulb.¹⁴ These signals also could originate from changes in the microenvironment instead of the melanoma cells themselves.⁶ Another possible mechanism is that repigmentation was caused by melanin-producing malignant melanocytes.⁴

Because this phenomenon typically occurs in older patients, the cause of repigmentation also could be related to chronic sun damage, which may result in upregulation of stem cell factor and α-melanocyte–stimulating hormone, as well as other molecules associated with melanogenesis, such as c-KIT receptor and tyrosinase.^15,16 Upregulation of these molecules can lead to an increased number of melanocytes within the hair bulb. In addition, UVA and narrowband UVB have been recognized as major players in melanocyte stimulation. Phototherapy with UVA or narrowband UVB has been used for repigmentation in vitiligo patients.¹⁷

 

In cases without invasion of hair follicles by malignant cells, repigmentation more likely results from external signals stimulating benign bulbar melanocytes to produce melanin rather than melanoma cell growth extending into the hair bulb.⁶ In these cases, there is an increase in the number of hair bulbar melanocytes with a lack of malignant morphology in the hair bulb.⁸ If the signals are directly from melanoma cells in the hair bulb, it is unknown how the malignant cells upregulated melanogenesis in adjacent benign melanocytes or which specific signals required for normal pigmentation were involved in these repigmentation cases.⁶

Use of medications was ruled out as an underlying cause of the repigmentation in our patient. Drug-related repigmentation of the hair typically is observed in a diffuse generalized pattern. In our case, the repigmentation was localized to the area of the underlying dark patch, and the patient was not on any medications that could cause hair hyperpigmentation. Hyperpigmentation has been associated with acitretin, lenalidomide, corticosteroids, erlotinib, latanoprost, verapamil, tamoxifen, levodopa, thalidomide, PD-1 inhibitors, and tumor necrosis α inhibitors.^18-30 Repigmentation also has been reported after local radiotherapy and herpes zoster infection.^31,32

The underlying melanoma in our patient was removed by staged square excision. Excision was the treatment of choice for most similar reported cases. Radiotherapy was utilized in two different cases.^3,4 In one case, radiotherapy was successfully used to treat melanoma in situ, lentigo maligna type; the patient’s hair grew back to its original color, which suggests that normal hair physiology was restored once melanoma cells were eliminated.³ One reported case demonstrated successful treatment of lentigo maligna type–melanoma with imiquimod cream 5% applied 6 times weekly for 9 months with a positive cosmetic result.⁹ The exact mechanism of imiquimod is not fully understood. Imiquimod induces cytokines to stimulate the production of IFN-α via activation of toll-like receptor 7.³³ There was complete clearing of the lesion as well as the hair pigmentation,⁹ which suggests that the treatment also eliminated deeper cells influencing pigmentation. A case of malignant amelanotic melanoma was successfully treated with anti–PD-1 antibody pembrolizumab (2 mg/kg every 3 weeks), with no recurrence at 12 months. Pembrolizumab acts as an immune checkpoint inhibitor by binding to the PD-1 receptor and allowing the immune system to recognize and attack melanoma cells. After 5 doses of pembrolizumab, the patient was clear of disease and his hair color returned to gray.⁵

In 2022, melanoma was estimated to be the fifth most commonly diagnosed cancer among men and women in the United States.³⁴ Early melanoma detection is a critical factor in achieving positive patient outcomes. Hair repigmentation is a potentially serious phenomenon that warrants a physician visit. Melanoma lesions under the hair may be overlooked because of limited visibility. Physicians must inspect spontaneous hair repigmentation with high suspicion and interpret the change as a possible indirect result of melanoma. Overall, it is important to increase public awareness of regular skin checks and melanoma warning signs.

To the Editor:

An 85-year-old man with a history of hypertension and chronic kidney disease presented with a localized darkening patch of hair on the left parietal scalp that had progressed over the last 7 years (Figure 1A). He had no prior history of skin cancer. Physical examination revealed the remainder of the hair was gray. There was an irregularly pigmented plaque on the skin underlying the darkened hair measuring 5.0 cm in diameter that was confirmed to be melanoma (Figure 1B). He underwent a staged excision to remove the lesion. The surgical defect was closed via a 5.0×6.0-cm full-thickness skin graft. 

The initial biopsy showed melanoma in situ. However, the final pathology report following the excision revealed an invasive melanoma with a Breslow depth of 1.0 mm (Clark level IV; American Joint Committee on Cancer T1b).¹ Histopathology showed pigment deposition with surrounding deep follicular extension of melanoma (Figure 2).

The patient declined a sentinel lymph node biopsy and agreed to a genetic profile assessment.² The results of the test identified the patient had a low probability of a positive sentinel lymph node and the lowest risk of melanoma recurrence within 5 years. The patient was clear of disease at 12-month follow-up.

Based on a PubMed search of articles indexed for MEDLINE using the terms hair repigmentation and melanoma, there have been 11 other reported cases of hair repigmentation associated with melanoma (Table).^3-13 It initially was suspected that this rare phenomenon primarily existed in the female population, as the first 5 cases were reported solely in females,^3-7 possibly due to the prevalence of androgenetic alopecia in males.¹¹ However, 6 cases of repigmentation associated with melanoma were later reported in males^8-13; our patient represents an additional reported case in a male. It is unknown if there is a higher prevalence of this phenomenon among males or females.

Most previously reported cases of repigmentation were associated with melanoma in situ, lentigo maligna type. Repigmentation also has been reported in malignant melanoma, as documented in our patient, as well as desmoplastic and amelanotic melanoma.^5,6 In every case, the color of the repigmentation was darker than the rest of the patient’s hair; however, the repigmentation color can be different from the patient’s original hair color from their youth.^4,5,11

The exact mechanism responsible for hair repigmentation in the setting of melanoma is unclear. It has been speculated from prior cases that repigmentation may be caused by paracrine stimulation from melanoma cells activating adjacent benign hair follicle melanocytes to produce melanin.^7,14,15 This process likely is due to cytokines or growth factors, such as c-kit ligand.^14,15 Several neural and immune networks and mediators activate the receptor tyrosine kinase KIT, which is thought to play a role in activating melanogenesis within the hair bulb.¹⁴ These signals also could originate from changes in the microenvironment instead of the melanoma cells themselves.⁶ Another possible mechanism is that repigmentation was caused by melanin-producing malignant melanocytes.⁴

Because this phenomenon typically occurs in older patients, the cause of repigmentation also could be related to chronic sun damage, which may result in upregulation of stem cell factor and α-melanocyte–stimulating hormone, as well as other molecules associated with melanogenesis, such as c-KIT receptor and tyrosinase.^15,16 Upregulation of these molecules can lead to an increased number of melanocytes within the hair bulb. In addition, UVA and narrowband UVB have been recognized as major players in melanocyte stimulation. Phototherapy with UVA or narrowband UVB has been used for repigmentation in vitiligo patients.¹⁷

 

In cases without invasion of hair follicles by malignant cells, repigmentation more likely results from external signals stimulating benign bulbar melanocytes to produce melanin rather than melanoma cell growth extending into the hair bulb.⁶ In these cases, there is an increase in the number of hair bulbar melanocytes with a lack of malignant morphology in the hair bulb.⁸ If the signals are directly from melanoma cells in the hair bulb, it is unknown how the malignant cells upregulated melanogenesis in adjacent benign melanocytes or which specific signals required for normal pigmentation were involved in these repigmentation cases.⁶

Use of medications was ruled out as an underlying cause of the repigmentation in our patient. Drug-related repigmentation of the hair typically is observed in a diffuse generalized pattern. In our case, the repigmentation was localized to the area of the underlying dark patch, and the patient was not on any medications that could cause hair hyperpigmentation. Hyperpigmentation has been associated with acitretin, lenalidomide, corticosteroids, erlotinib, latanoprost, verapamil, tamoxifen, levodopa, thalidomide, PD-1 inhibitors, and tumor necrosis α inhibitors.^18-30 Repigmentation also has been reported after local radiotherapy and herpes zoster infection.^31,32

The underlying melanoma in our patient was removed by staged square excision. Excision was the treatment of choice for most similar reported cases. Radiotherapy was utilized in two different cases.^3,4 In one case, radiotherapy was successfully used to treat melanoma in situ, lentigo maligna type; the patient’s hair grew back to its original color, which suggests that normal hair physiology was restored once melanoma cells were eliminated.³ One reported case demonstrated successful treatment of lentigo maligna type–melanoma with imiquimod cream 5% applied 6 times weekly for 9 months with a positive cosmetic result.⁹ The exact mechanism of imiquimod is not fully understood. Imiquimod induces cytokines to stimulate the production of IFN-α via activation of toll-like receptor 7.³³ There was complete clearing of the lesion as well as the hair pigmentation,⁹ which suggests that the treatment also eliminated deeper cells influencing pigmentation. A case of malignant amelanotic melanoma was successfully treated with anti–PD-1 antibody pembrolizumab (2 mg/kg every 3 weeks), with no recurrence at 12 months. Pembrolizumab acts as an immune checkpoint inhibitor by binding to the PD-1 receptor and allowing the immune system to recognize and attack melanoma cells. After 5 doses of pembrolizumab, the patient was clear of disease and his hair color returned to gray.⁵

In 2022, melanoma was estimated to be the fifth most commonly diagnosed cancer among men and women in the United States.³⁴ Early melanoma detection is a critical factor in achieving positive patient outcomes. Hair repigmentation is a potentially serious phenomenon that warrants a physician visit. Melanoma lesions under the hair may be overlooked because of limited visibility. Physicians must inspect spontaneous hair repigmentation with high suspicion and interpret the change as a possible indirect result of melanoma. Overall, it is important to increase public awareness of regular skin checks and melanoma warning signs.

To the Editor:

Generalized essential telangiectasia (GET) is a rare, benign, and progressive primary cutaneous disease manifesting as telangiectases of the skin without systemic symptoms. It is unique in that it has widespread distribution on the body. Generalized essential telangiectasia more commonly affects women, usually in the fourth decade of life. The telangiectases most frequently appear on the legs, advancing over time to involve the trunk and arms and presenting in several patterns, including diffuse, macular, plaquelike, discrete, or confluent. Although GET typically is asymptomatic, numbness, tingling, and burning of the involved areas have been reported.¹ Treatment modalities for GET vary, though pulsed dye laser (PDL) therapy is most common. We report the case of a 40-year-old woman with a 5-year history of GET who was treated successfully with PDL.

A 40-year-old woman presented to our dermatology clinic with progressive prominence of blood vessels involving the dorsal aspects of the feet of 5 years’ duration. The prominent vessels had spread to involve the legs (Figure 1), buttocks, lower abdomen, forearms, and medial upper arms. The patient denied any personal history of bleeding disorders or family history of inherited conditions associated with visceral vascular malformations, such as hereditary hemorrhagic telangiectasia. Notably, magnetic resonance imaging of the liver approximately 3 weeks prior to initiating treatment with PDL demonstrated multiple hepatic lesions consistent with hemangiomas. The patient reported an occasional tingling sensation in the feet. She was otherwise asymptomatic but did report psychological distress associated with the skin changes.

Punch biopsies from the right lower leg and right buttock demonstrated increased vascularity of the dermis, a mild superficial perivascular lymphocytic infiltrate, and mild edema of the upper dermis without evidence of vasculitis. Autoimmune and coagulopathy workups were negative. The clinical and pathological findings were most consistent with GET.

Over the next 2.5 years, the patient underwent treatment with doxycycline and a series of 16 treatments with PDL (fluence, 6–12 J/cm²; pulse width, 10 milliseconds) with a positive cosmetic response. Considerable improvement in the lower legs was noted after 2 years of treatment with PDL (Figure 2).

Recurrence of GET was noted between PDL treatments, which led to progression of the disease process; all treated sites showed slow recurrence of lesions within several months after treatment. After 2 years, doxycycline was discontinued because of a perceived lack of continued benefit and the patient’s desire for alternative therapy. She was started on a 3-month trial of supplementation with ascorbic acid and rutin (or rutoside, a bioflavinoid), without noticeable improvement.

The diffuse distribution of dramatic telangiectases in GET makes treatment difficult. Standard treatments are not well established or studied due to the rarity of the condition. A review of PubMed articles indexed for MEDLINE using the terms treatment and generalized essential telangiectasias demonstrated several attempted treatment modalities for GET with varying success. In 4 cases in which PDL was used,^2-5 a positive cosmetic response was noted, similar to what was seen in our patient. In 1 of the 4 cases, conservative management with ascorbic acid and compression stockings was unsuccessful; however, 6-mercaptopurine, used to treat that patient’s ulcerative colitis, incidentally resulted in resolution of GET.² In 2 cases, response was maintained at 1.5-year follow-up.^3,5 Two cases noted successful treatment with acyclovir,^6,7 and 2 more demonstrated successful treatment with systemic ketoconazole.^6,8 Some improvement was reported with oral doxycycline or tetracycline in 2 cases.^9,10 Sclerotherapy improved the cosmetic appearance of telangiectases in one patient but was unsustainable because of the pain associated with the procedure.¹¹ Nd:YAG laser therapy was effective in one case¹²; however, the patient experienced relapse at 6-month follow-up—similar to what we observed in our patient. Three patients treated with intense pulsed light therapy experienced results that were maintained at 2-year follow-up.¹³

Generalized essential telangiectasia generally is considered a skin-limited disease without systemic manifestations, but 2 reports^11,14 described its association with gastric antral vascular ectasia—known as watermelon stomach. Hepatic hemangiomas are the most common benign liver lesions; however, the findings on magnetic resonance imaging in our patient, in combination with the 2 reported cases of watermelon stomach, suggest that the vascular changes of GET might extend below the skin.

Of the cases we reviewed, our patient had the longest reported duration of PDL treatment and follow-up for GET in which a successful, albeit transient, response was demonstrated. Our review of the literature revealed other reports of success with PDL and intense pulsed light therapy; results were maintained in some patients, while disease relapsed in others. Further studies are needed to understand why results are maintained in some but not all patients.

Although the cost of PDL as a cosmetic procedure must be taken into consideration when planning treatment of GET, we conclude that it is a safe option that can be effective until other treatment options are established to control the disease.

To the Editor:

Generalized essential telangiectasia (GET) is a rare, benign, and progressive primary cutaneous disease manifesting as telangiectases of the skin without systemic symptoms. It is unique in that it has widespread distribution on the body. Generalized essential telangiectasia more commonly affects women, usually in the fourth decade of life. The telangiectases most frequently appear on the legs, advancing over time to involve the trunk and arms and presenting in several patterns, including diffuse, macular, plaquelike, discrete, or confluent. Although GET typically is asymptomatic, numbness, tingling, and burning of the involved areas have been reported.¹ Treatment modalities for GET vary, though pulsed dye laser (PDL) therapy is most common. We report the case of a 40-year-old woman with a 5-year history of GET who was treated successfully with PDL.

A 40-year-old woman presented to our dermatology clinic with progressive prominence of blood vessels involving the dorsal aspects of the feet of 5 years’ duration. The prominent vessels had spread to involve the legs (Figure 1), buttocks, lower abdomen, forearms, and medial upper arms. The patient denied any personal history of bleeding disorders or family history of inherited conditions associated with visceral vascular malformations, such as hereditary hemorrhagic telangiectasia. Notably, magnetic resonance imaging of the liver approximately 3 weeks prior to initiating treatment with PDL demonstrated multiple hepatic lesions consistent with hemangiomas. The patient reported an occasional tingling sensation in the feet. She was otherwise asymptomatic but did report psychological distress associated with the skin changes.

Punch biopsies from the right lower leg and right buttock demonstrated increased vascularity of the dermis, a mild superficial perivascular lymphocytic infiltrate, and mild edema of the upper dermis without evidence of vasculitis. Autoimmune and coagulopathy workups were negative. The clinical and pathological findings were most consistent with GET.

Over the next 2.5 years, the patient underwent treatment with doxycycline and a series of 16 treatments with PDL (fluence, 6–12 J/cm²; pulse width, 10 milliseconds) with a positive cosmetic response. Considerable improvement in the lower legs was noted after 2 years of treatment with PDL (Figure 2).

Recurrence of GET was noted between PDL treatments, which led to progression of the disease process; all treated sites showed slow recurrence of lesions within several months after treatment. After 2 years, doxycycline was discontinued because of a perceived lack of continued benefit and the patient’s desire for alternative therapy. She was started on a 3-month trial of supplementation with ascorbic acid and rutin (or rutoside, a bioflavinoid), without noticeable improvement.

The diffuse distribution of dramatic telangiectases in GET makes treatment difficult. Standard treatments are not well established or studied due to the rarity of the condition. A review of PubMed articles indexed for MEDLINE using the terms treatment and generalized essential telangiectasias demonstrated several attempted treatment modalities for GET with varying success. In 4 cases in which PDL was used,^2-5 a positive cosmetic response was noted, similar to what was seen in our patient. In 1 of the 4 cases, conservative management with ascorbic acid and compression stockings was unsuccessful; however, 6-mercaptopurine, used to treat that patient’s ulcerative colitis, incidentally resulted in resolution of GET.² In 2 cases, response was maintained at 1.5-year follow-up.^3,5 Two cases noted successful treatment with acyclovir,^6,7 and 2 more demonstrated successful treatment with systemic ketoconazole.^6,8 Some improvement was reported with oral doxycycline or tetracycline in 2 cases.^9,10 Sclerotherapy improved the cosmetic appearance of telangiectases in one patient but was unsustainable because of the pain associated with the procedure.¹¹ Nd:YAG laser therapy was effective in one case¹²; however, the patient experienced relapse at 6-month follow-up—similar to what we observed in our patient. Three patients treated with intense pulsed light therapy experienced results that were maintained at 2-year follow-up.¹³

Generalized essential telangiectasia generally is considered a skin-limited disease without systemic manifestations, but 2 reports^11,14 described its association with gastric antral vascular ectasia—known as watermelon stomach. Hepatic hemangiomas are the most common benign liver lesions; however, the findings on magnetic resonance imaging in our patient, in combination with the 2 reported cases of watermelon stomach, suggest that the vascular changes of GET might extend below the skin.

Of the cases we reviewed, our patient had the longest reported duration of PDL treatment and follow-up for GET in which a successful, albeit transient, response was demonstrated. Our review of the literature revealed other reports of success with PDL and intense pulsed light therapy; results were maintained in some patients, while disease relapsed in others. Further studies are needed to understand why results are maintained in some but not all patients.

Although the cost of PDL as a cosmetic procedure must be taken into consideration when planning treatment of GET, we conclude that it is a safe option that can be effective until other treatment options are established to control the disease.

To the Editor:

Generalized essential telangiectasia (GET) is a rare, benign, and progressive primary cutaneous disease manifesting as telangiectases of the skin without systemic symptoms. It is unique in that it has widespread distribution on the body. Generalized essential telangiectasia more commonly affects women, usually in the fourth decade of life. The telangiectases most frequently appear on the legs, advancing over time to involve the trunk and arms and presenting in several patterns, including diffuse, macular, plaquelike, discrete, or confluent. Although GET typically is asymptomatic, numbness, tingling, and burning of the involved areas have been reported.¹ Treatment modalities for GET vary, though pulsed dye laser (PDL) therapy is most common. We report the case of a 40-year-old woman with a 5-year history of GET who was treated successfully with PDL.

A 40-year-old woman presented to our dermatology clinic with progressive prominence of blood vessels involving the dorsal aspects of the feet of 5 years’ duration. The prominent vessels had spread to involve the legs (Figure 1), buttocks, lower abdomen, forearms, and medial upper arms. The patient denied any personal history of bleeding disorders or family history of inherited conditions associated with visceral vascular malformations, such as hereditary hemorrhagic telangiectasia. Notably, magnetic resonance imaging of the liver approximately 3 weeks prior to initiating treatment with PDL demonstrated multiple hepatic lesions consistent with hemangiomas. The patient reported an occasional tingling sensation in the feet. She was otherwise asymptomatic but did report psychological distress associated with the skin changes.

Punch biopsies from the right lower leg and right buttock demonstrated increased vascularity of the dermis, a mild superficial perivascular lymphocytic infiltrate, and mild edema of the upper dermis without evidence of vasculitis. Autoimmune and coagulopathy workups were negative. The clinical and pathological findings were most consistent with GET.

Over the next 2.5 years, the patient underwent treatment with doxycycline and a series of 16 treatments with PDL (fluence, 6–12 J/cm²; pulse width, 10 milliseconds) with a positive cosmetic response. Considerable improvement in the lower legs was noted after 2 years of treatment with PDL (Figure 2).

Recurrence of GET was noted between PDL treatments, which led to progression of the disease process; all treated sites showed slow recurrence of lesions within several months after treatment. After 2 years, doxycycline was discontinued because of a perceived lack of continued benefit and the patient’s desire for alternative therapy. She was started on a 3-month trial of supplementation with ascorbic acid and rutin (or rutoside, a bioflavinoid), without noticeable improvement.

The diffuse distribution of dramatic telangiectases in GET makes treatment difficult. Standard treatments are not well established or studied due to the rarity of the condition. A review of PubMed articles indexed for MEDLINE using the terms treatment and generalized essential telangiectasias demonstrated several attempted treatment modalities for GET with varying success. In 4 cases in which PDL was used,^2-5 a positive cosmetic response was noted, similar to what was seen in our patient. In 1 of the 4 cases, conservative management with ascorbic acid and compression stockings was unsuccessful; however, 6-mercaptopurine, used to treat that patient’s ulcerative colitis, incidentally resulted in resolution of GET.² In 2 cases, response was maintained at 1.5-year follow-up.^3,5 Two cases noted successful treatment with acyclovir,^6,7 and 2 more demonstrated successful treatment with systemic ketoconazole.^6,8 Some improvement was reported with oral doxycycline or tetracycline in 2 cases.^9,10 Sclerotherapy improved the cosmetic appearance of telangiectases in one patient but was unsustainable because of the pain associated with the procedure.¹¹ Nd:YAG laser therapy was effective in one case¹²; however, the patient experienced relapse at 6-month follow-up—similar to what we observed in our patient. Three patients treated with intense pulsed light therapy experienced results that were maintained at 2-year follow-up.¹³

Generalized essential telangiectasia generally is considered a skin-limited disease without systemic manifestations, but 2 reports^11,14 described its association with gastric antral vascular ectasia—known as watermelon stomach. Hepatic hemangiomas are the most common benign liver lesions; however, the findings on magnetic resonance imaging in our patient, in combination with the 2 reported cases of watermelon stomach, suggest that the vascular changes of GET might extend below the skin.

Of the cases we reviewed, our patient had the longest reported duration of PDL treatment and follow-up for GET in which a successful, albeit transient, response was demonstrated. Our review of the literature revealed other reports of success with PDL and intense pulsed light therapy; results were maintained in some patients, while disease relapsed in others. Further studies are needed to understand why results are maintained in some but not all patients.

Although the cost of PDL as a cosmetic procedure must be taken into consideration when planning treatment of GET, we conclude that it is a safe option that can be effective until other treatment options are established to control the disease.

To the Editor:

Fat necrosis of the breast is a benign inflammatory disease of adipose tissue commonly observed after trauma in the female breast during the perimenopausal period.¹ Fat necrosis of the male breast is rare, first described by Silverstone² in 1949; the condition usually presents with unilateral, painful or asymptomatic, firm nodules, which in rare cases are observed as skin retraction and thickening, ecchymosis, erythematous plaque–like cellulitis, local depression, and/or discoloration of the breast skin.^3-5

Diagnosis of fat necrosis of the male breast may need to be confirmed via biopsy in conjunction with clinical and radiologic findings because the condition can mimic breast cancer.¹ We report a case of bilateral fat necrosis of the breast mimicking breast cancer following wax hair removal.

A 42-year-old man presented to our outpatient dermatology clinic for evaluation of redness, swelling, and hardness of the skin of both breasts of 3 weeks’ duration. The patient had a history of wax hair removal of the entire anterior aspect of the body. He reported an erythematous, edematous, warm plaque that developed on the breasts 2 days after waxing. The plaque did not respond to antibiotics. The swelling and induration progressed over the 2 weeks after the patient was waxed. The patient had no family history of breast cancer. He had a standing diagnosis of gynecomastia. He denied any history of fat or filler injection in the affected area.

Dermatologic examination revealed erythematous, edematous, indurated, asymptomatic plaques with a peau d’orange appearance on the bilateral pectoral and presternal region. Minimal retraction of the right areola was noted (Figure 1). The bilateral axillary lymph nodes were palpable.

Laboratory results including erythrocyte sedimentation rate (108 mm/h [reference range, 2–20 mm/h]), C-reactive protein (9.2 mg/dL [reference range, >0.5 mg/dL]), and ferritin levels (645 μg/L [reference range, 13–500 μg/L]) were consistent with inflammation; testing also included white blood cell count (8.5×10³/μL [reference range, 4–10×10³/μL]), hemoglobin (9.6 g/dL [reference range, 12–16 g/dL]), platelet count (437×10³/μL [reference range, 100–400×10³/μL]), procalcitonin (0.2 ng/mL [reference range, <0.3 ng/mL]), vitamin B₁₂ (159 ng/L [reference range, 197–771 ng/L]), and folate (4.57 μg/L [reference range, 3.89–26.8 μg/L]). Other biochemical values were within reference range.

Mammography of both breasts revealed a Breast Imaging Reporting and Data System (BI-RADS) score of 4 with a suspicious abnormality (ie, diffuse edema of the breast, multiple calcifications in a nonspecific pattern, oil cysts with calcifications, and bilateral axillary lymphadenopathy with a diameter of 2.5 cm and a thick and irregular cortex)(Figure 2A). Ultrasonography of both breasts revealed an inflammatory breast. Magnetic resonance imaging showed similar findings with diffuse edema and a heterogeneous appearance. Contrast-enhanced magnetic resonance imaging showed diffuse contrast enhancement in both breasts extending to the pectoral muscles and axillary regions, consistent with inflammatory changes (Figure 2B).

Because of difficulty differentiating inflammation and an infiltrating tumor, histopathologic examination was recommended by radiology. Results from a 5-mm punch biopsy from the right breast yielded the following differential diagnoses: cellulitis, panniculitis, inflammatory breast cancer, subcutaneous fat necrosis, and paraffinoma. Histopathologic examination of the skin revealed a normal epidermis and a dense inflammatory cell infiltrate comprising lymphocytes and monocytes in the dermis and subcutaneous tissue. Marked fibrosis also was noted in the dermis and subcutaneous tissue. Lipophagic fat necrosis accompanied by a variable inflammatory cell infiltrate consisted of histiocytes and neutrophils (Figure 3A). Pankeratin immunostaining was negative. Fat necrosis was present in a biopsy specimen obtained from the right breast; no signs of malignancy were present (Figure 3B). Fine-needle aspiration of the axillary lymph nodes was benign. Given these histopathologic findings, malignancy was excluded from the differential diagnosis. Paraffinoma also was ruled out because the patient insistently denied any history of fat or filler injection.

Based on the clinical, histopathologic, and radiologic findings, as well as the history of minor trauma due to wax hair removal, a diagnosis of fat necrosis of the breast was made. Intervention was not recommended by the plastic surgeons who subsequently evaluated the patient, because the additional trauma may aggravate the lesion. He was treated with nonsteroidal anti-inflammatory drugs.

At 6-month follow-up, there was marked reduction in the erythema and edema but no notable improvement of the induration. A potent topical steroid was added to the treatment, but only slight regression of the induration was observed.

The normal male breast is comprised of fat and a few secretory ducts.⁶ Gynecomastia and breast cancer are the 2 most common conditions of the male breast; fat necrosis of the male breast is rare. In a study of 236 male patients with breast disease, only 5 had fat necrosis.⁷

Fat necrosis of the breast can be observed with various clinical and radiological presentations. Subcutaneous nodules, skin retraction and thickening, local skin depression, and ecchymosis are the more common presentations of fat necrosis.^3-5 In our case, the first symptoms of disease were similar to those seen in cellulitis. The presentation of fat necrosis–like cellulitis has been described only rarely in the medical literature. Haikin et al⁵ reported a case of fat necrosis of the leg in a child that presented with cellulitis followed by induration, which did not respond to antibiotics, as was the case with our patient.⁵

Blunt trauma, breast reduction surgery, and breast augmentation surgery can cause fat necrosis of the breast^1,4; in some cases, the cause cannot be determined.⁸ The only pertinent history in our patient was wax hair removal. Fat necrosis was an unexpected complication, but hair removal can be considered minor trauma; however, this is not commonly reported in the literature following hair removal with wax. In a study that reviewed diseases of the male breast, the investigators observed that all male patients with fat necrosis had pseudogynecomastia (adipomastia).⁷ Although our patient’s entire anterior trunk was epilated, only the breast was affected. This situation might be explained by underlying gynecomastia because fat necrosis is common in areas of the body where subcutaneous fat tissue is dense.

Fat necrosis of the breast can be mistaken—both clinically and radiologically—for malignancy, such as in our case. Diagnosis of fat necrosis of the breast should be a diagnosis of exclusion; therefore, histopathologic confirmation of the lesion is imperative.⁹

In conclusion, fat necrosis of the male breast is rare. The condition can present as cellulitis. Hair removal with wax might be a cause of fat necrosis. Because breast cancer and fat necrosis can exhibit clinical and radiologic similarities, the diagnosis of fat necrosis should be confirmed by histopathologic analysis in conjunction with clinical and radiologic findings.

To the Editor:

Fat necrosis of the breast is a benign inflammatory disease of adipose tissue commonly observed after trauma in the female breast during the perimenopausal period.¹ Fat necrosis of the male breast is rare, first described by Silverstone² in 1949; the condition usually presents with unilateral, painful or asymptomatic, firm nodules, which in rare cases are observed as skin retraction and thickening, ecchymosis, erythematous plaque–like cellulitis, local depression, and/or discoloration of the breast skin.^3-5

Diagnosis of fat necrosis of the male breast may need to be confirmed via biopsy in conjunction with clinical and radiologic findings because the condition can mimic breast cancer.¹ We report a case of bilateral fat necrosis of the breast mimicking breast cancer following wax hair removal.

A 42-year-old man presented to our outpatient dermatology clinic for evaluation of redness, swelling, and hardness of the skin of both breasts of 3 weeks’ duration. The patient had a history of wax hair removal of the entire anterior aspect of the body. He reported an erythematous, edematous, warm plaque that developed on the breasts 2 days after waxing. The plaque did not respond to antibiotics. The swelling and induration progressed over the 2 weeks after the patient was waxed. The patient had no family history of breast cancer. He had a standing diagnosis of gynecomastia. He denied any history of fat or filler injection in the affected area.

Dermatologic examination revealed erythematous, edematous, indurated, asymptomatic plaques with a peau d’orange appearance on the bilateral pectoral and presternal region. Minimal retraction of the right areola was noted (Figure 1). The bilateral axillary lymph nodes were palpable.

Laboratory results including erythrocyte sedimentation rate (108 mm/h [reference range, 2–20 mm/h]), C-reactive protein (9.2 mg/dL [reference range, >0.5 mg/dL]), and ferritin levels (645 μg/L [reference range, 13–500 μg/L]) were consistent with inflammation; testing also included white blood cell count (8.5×10³/μL [reference range, 4–10×10³/μL]), hemoglobin (9.6 g/dL [reference range, 12–16 g/dL]), platelet count (437×10³/μL [reference range, 100–400×10³/μL]), procalcitonin (0.2 ng/mL [reference range, <0.3 ng/mL]), vitamin B₁₂ (159 ng/L [reference range, 197–771 ng/L]), and folate (4.57 μg/L [reference range, 3.89–26.8 μg/L]). Other biochemical values were within reference range.

Mammography of both breasts revealed a Breast Imaging Reporting and Data System (BI-RADS) score of 4 with a suspicious abnormality (ie, diffuse edema of the breast, multiple calcifications in a nonspecific pattern, oil cysts with calcifications, and bilateral axillary lymphadenopathy with a diameter of 2.5 cm and a thick and irregular cortex)(Figure 2A). Ultrasonography of both breasts revealed an inflammatory breast. Magnetic resonance imaging showed similar findings with diffuse edema and a heterogeneous appearance. Contrast-enhanced magnetic resonance imaging showed diffuse contrast enhancement in both breasts extending to the pectoral muscles and axillary regions, consistent with inflammatory changes (Figure 2B).

Because of difficulty differentiating inflammation and an infiltrating tumor, histopathologic examination was recommended by radiology. Results from a 5-mm punch biopsy from the right breast yielded the following differential diagnoses: cellulitis, panniculitis, inflammatory breast cancer, subcutaneous fat necrosis, and paraffinoma. Histopathologic examination of the skin revealed a normal epidermis and a dense inflammatory cell infiltrate comprising lymphocytes and monocytes in the dermis and subcutaneous tissue. Marked fibrosis also was noted in the dermis and subcutaneous tissue. Lipophagic fat necrosis accompanied by a variable inflammatory cell infiltrate consisted of histiocytes and neutrophils (Figure 3A). Pankeratin immunostaining was negative. Fat necrosis was present in a biopsy specimen obtained from the right breast; no signs of malignancy were present (Figure 3B). Fine-needle aspiration of the axillary lymph nodes was benign. Given these histopathologic findings, malignancy was excluded from the differential diagnosis. Paraffinoma also was ruled out because the patient insistently denied any history of fat or filler injection.

Based on the clinical, histopathologic, and radiologic findings, as well as the history of minor trauma due to wax hair removal, a diagnosis of fat necrosis of the breast was made. Intervention was not recommended by the plastic surgeons who subsequently evaluated the patient, because the additional trauma may aggravate the lesion. He was treated with nonsteroidal anti-inflammatory drugs.

At 6-month follow-up, there was marked reduction in the erythema and edema but no notable improvement of the induration. A potent topical steroid was added to the treatment, but only slight regression of the induration was observed.

The normal male breast is comprised of fat and a few secretory ducts.⁶ Gynecomastia and breast cancer are the 2 most common conditions of the male breast; fat necrosis of the male breast is rare. In a study of 236 male patients with breast disease, only 5 had fat necrosis.⁷

Fat necrosis of the breast can be observed with various clinical and radiological presentations. Subcutaneous nodules, skin retraction and thickening, local skin depression, and ecchymosis are the more common presentations of fat necrosis.^3-5 In our case, the first symptoms of disease were similar to those seen in cellulitis. The presentation of fat necrosis–like cellulitis has been described only rarely in the medical literature. Haikin et al⁵ reported a case of fat necrosis of the leg in a child that presented with cellulitis followed by induration, which did not respond to antibiotics, as was the case with our patient.⁵

Blunt trauma, breast reduction surgery, and breast augmentation surgery can cause fat necrosis of the breast^1,4; in some cases, the cause cannot be determined.⁸ The only pertinent history in our patient was wax hair removal. Fat necrosis was an unexpected complication, but hair removal can be considered minor trauma; however, this is not commonly reported in the literature following hair removal with wax. In a study that reviewed diseases of the male breast, the investigators observed that all male patients with fat necrosis had pseudogynecomastia (adipomastia).⁷ Although our patient’s entire anterior trunk was epilated, only the breast was affected. This situation might be explained by underlying gynecomastia because fat necrosis is common in areas of the body where subcutaneous fat tissue is dense.

Fat necrosis of the breast can be mistaken—both clinically and radiologically—for malignancy, such as in our case. Diagnosis of fat necrosis of the breast should be a diagnosis of exclusion; therefore, histopathologic confirmation of the lesion is imperative.⁹

In conclusion, fat necrosis of the male breast is rare. The condition can present as cellulitis. Hair removal with wax might be a cause of fat necrosis. Because breast cancer and fat necrosis can exhibit clinical and radiologic similarities, the diagnosis of fat necrosis should be confirmed by histopathologic analysis in conjunction with clinical and radiologic findings.

To the Editor:

Fat necrosis of the breast is a benign inflammatory disease of adipose tissue commonly observed after trauma in the female breast during the perimenopausal period.¹ Fat necrosis of the male breast is rare, first described by Silverstone² in 1949; the condition usually presents with unilateral, painful or asymptomatic, firm nodules, which in rare cases are observed as skin retraction and thickening, ecchymosis, erythematous plaque–like cellulitis, local depression, and/or discoloration of the breast skin.^3-5

Diagnosis of fat necrosis of the male breast may need to be confirmed via biopsy in conjunction with clinical and radiologic findings because the condition can mimic breast cancer.¹ We report a case of bilateral fat necrosis of the breast mimicking breast cancer following wax hair removal.

A 42-year-old man presented to our outpatient dermatology clinic for evaluation of redness, swelling, and hardness of the skin of both breasts of 3 weeks’ duration. The patient had a history of wax hair removal of the entire anterior aspect of the body. He reported an erythematous, edematous, warm plaque that developed on the breasts 2 days after waxing. The plaque did not respond to antibiotics. The swelling and induration progressed over the 2 weeks after the patient was waxed. The patient had no family history of breast cancer. He had a standing diagnosis of gynecomastia. He denied any history of fat or filler injection in the affected area.

Dermatologic examination revealed erythematous, edematous, indurated, asymptomatic plaques with a peau d’orange appearance on the bilateral pectoral and presternal region. Minimal retraction of the right areola was noted (Figure 1). The bilateral axillary lymph nodes were palpable.

Laboratory results including erythrocyte sedimentation rate (108 mm/h [reference range, 2–20 mm/h]), C-reactive protein (9.2 mg/dL [reference range, >0.5 mg/dL]), and ferritin levels (645 μg/L [reference range, 13–500 μg/L]) were consistent with inflammation; testing also included white blood cell count (8.5×10³/μL [reference range, 4–10×10³/μL]), hemoglobin (9.6 g/dL [reference range, 12–16 g/dL]), platelet count (437×10³/μL [reference range, 100–400×10³/μL]), procalcitonin (0.2 ng/mL [reference range, <0.3 ng/mL]), vitamin B₁₂ (159 ng/L [reference range, 197–771 ng/L]), and folate (4.57 μg/L [reference range, 3.89–26.8 μg/L]). Other biochemical values were within reference range.

Mammography of both breasts revealed a Breast Imaging Reporting and Data System (BI-RADS) score of 4 with a suspicious abnormality (ie, diffuse edema of the breast, multiple calcifications in a nonspecific pattern, oil cysts with calcifications, and bilateral axillary lymphadenopathy with a diameter of 2.5 cm and a thick and irregular cortex)(Figure 2A). Ultrasonography of both breasts revealed an inflammatory breast. Magnetic resonance imaging showed similar findings with diffuse edema and a heterogeneous appearance. Contrast-enhanced magnetic resonance imaging showed diffuse contrast enhancement in both breasts extending to the pectoral muscles and axillary regions, consistent with inflammatory changes (Figure 2B).

Because of difficulty differentiating inflammation and an infiltrating tumor, histopathologic examination was recommended by radiology. Results from a 5-mm punch biopsy from the right breast yielded the following differential diagnoses: cellulitis, panniculitis, inflammatory breast cancer, subcutaneous fat necrosis, and paraffinoma. Histopathologic examination of the skin revealed a normal epidermis and a dense inflammatory cell infiltrate comprising lymphocytes and monocytes in the dermis and subcutaneous tissue. Marked fibrosis also was noted in the dermis and subcutaneous tissue. Lipophagic fat necrosis accompanied by a variable inflammatory cell infiltrate consisted of histiocytes and neutrophils (Figure 3A). Pankeratin immunostaining was negative. Fat necrosis was present in a biopsy specimen obtained from the right breast; no signs of malignancy were present (Figure 3B). Fine-needle aspiration of the axillary lymph nodes was benign. Given these histopathologic findings, malignancy was excluded from the differential diagnosis. Paraffinoma also was ruled out because the patient insistently denied any history of fat or filler injection.

Based on the clinical, histopathologic, and radiologic findings, as well as the history of minor trauma due to wax hair removal, a diagnosis of fat necrosis of the breast was made. Intervention was not recommended by the plastic surgeons who subsequently evaluated the patient, because the additional trauma may aggravate the lesion. He was treated with nonsteroidal anti-inflammatory drugs.

At 6-month follow-up, there was marked reduction in the erythema and edema but no notable improvement of the induration. A potent topical steroid was added to the treatment, but only slight regression of the induration was observed.

The normal male breast is comprised of fat and a few secretory ducts.⁶ Gynecomastia and breast cancer are the 2 most common conditions of the male breast; fat necrosis of the male breast is rare. In a study of 236 male patients with breast disease, only 5 had fat necrosis.⁷

Fat necrosis of the breast can be observed with various clinical and radiological presentations. Subcutaneous nodules, skin retraction and thickening, local skin depression, and ecchymosis are the more common presentations of fat necrosis.^3-5 In our case, the first symptoms of disease were similar to those seen in cellulitis. The presentation of fat necrosis–like cellulitis has been described only rarely in the medical literature. Haikin et al⁵ reported a case of fat necrosis of the leg in a child that presented with cellulitis followed by induration, which did not respond to antibiotics, as was the case with our patient.⁵

Blunt trauma, breast reduction surgery, and breast augmentation surgery can cause fat necrosis of the breast^1,4; in some cases, the cause cannot be determined.⁸ The only pertinent history in our patient was wax hair removal. Fat necrosis was an unexpected complication, but hair removal can be considered minor trauma; however, this is not commonly reported in the literature following hair removal with wax. In a study that reviewed diseases of the male breast, the investigators observed that all male patients with fat necrosis had pseudogynecomastia (adipomastia).⁷ Although our patient’s entire anterior trunk was epilated, only the breast was affected. This situation might be explained by underlying gynecomastia because fat necrosis is common in areas of the body where subcutaneous fat tissue is dense.

Fat necrosis of the breast can be mistaken—both clinically and radiologically—for malignancy, such as in our case. Diagnosis of fat necrosis of the breast should be a diagnosis of exclusion; therefore, histopathologic confirmation of the lesion is imperative.⁹

In conclusion, fat necrosis of the male breast is rare. The condition can present as cellulitis. Hair removal with wax might be a cause of fat necrosis. Because breast cancer and fat necrosis can exhibit clinical and radiologic similarities, the diagnosis of fat necrosis should be confirmed by histopathologic analysis in conjunction with clinical and radiologic findings.

To the Editor:

Cyclosporine is an immunomodulatory medication that impacts T-lymphocyte function through calcineurin inhibition and suppression of IL-2 expression. Oral cyclosporine at low doses (1–3 mg/kg/d) is one of the more common systemic treatment options for moderate to severe atopic dermatitis. At these doses it has been shown to have therapeutic benefit in several skin conditions, including chronic spontaneous urticaria,¹ psoriasis,² and atopic dermatitis.³ When used at higher doses for conditions such as glomerulonephritis or transplantation, adverse effects may be notable, and close monitoring of drug metabolism as well as end-organ function is required. In contrast, severe adverse effects are uncommon with the lower doses of cyclosporine used for cutaneous conditions, and monitoring serum drug levels is not routinely practiced.⁴

A 58-year-old man was referred to clinic with severe atopic dermatitis refractory to maximal topical therapy prescribed by an outside physician. He was started on cyclosporine as an anticipated bridge to dupilumab biologic therapy. He had no history of hypertension, renal disease, or hepatic insufficiency prior to starting therapy. He demonstrated notable clinical improvement at a cyclosporine dosage of 300 mg/d (equating to 3.7 mg/kg/d). Three months after initiation of therapy, the patient presented to a local emergency department with new-onset seizurelike activity, confusion, and agitation. He was normotensive with clinical concern for status epilepticus. An initial laboratory assessment included a complete blood cell count, serum electrolyte panel, and urine toxicology screen, which were unremarkable. Computed tomography of the head showed confluent white-matter hypodensities in the left parietal-temporal-occipital lobes. Magnetic resonance imaging (MRI) of the brain showed innumerable peripherally distributed foci of microhemorrhage and vasogenic edema within the left parietal-temporal-occipital lobes (Figure).

He was intubated and sedated with admission to the medical intensive care unit, where a random cyclosporine level drawn approximately 9 hours after the prior dose was noted to be 263 ng/mL. Although target therapeutic levels for cyclosporine vary based on indication, toxic supratherapeutic levels generally are considered to be greater than 400 ng/mL.⁵ He had no evidence of acute kidney injury, uremia, or hypertension throughout hospitalization. An electroencephalogram showed left parieto-occipital periodic epileptiform discharges with generalized slowing. Cyclosporine was discontinued, and he was started on levetiracetam. His clinical and neuroimaging findings improved over the course of the 1-week hospitalization without any further intervention. Four weeks after hospitalization, he had full neurologic, electroencephalogram, and imaging recovery. Based on the presenting symptoms, transient neuroimaging findings, and full recovery with discontinuation of cyclosporine, the patient was diagnosed with cyclosporine-induced posterior reversible encephalopathy syndrome (PRES).

The diagnosis of PRES requires evidence of acute neurologic symptoms and radiographic findings of cortical/subcortical white-matter changes on computed tomography or MRI consistent with edema. The pathophysiology is not fully understood but appears to be related to vasogenic edema, primarily impacting the posterior aspect of the brain. There have been many reported offending agents, and symptoms typically resolve following cessation of these medications. Cases of cyclosporine-induced PRES have been reported, but most occurred at higher doses within weeks of medication initiation. Two cases of cyclosporine-induced PRES treated with cutaneous dosing have been reported; neither patient was taking it for atopic dermatitis.⁶

Cyclosporine-induced PRES remains a pathophysiologic conundrum. However, there is evidence to support direct endothelial damage causing cellular apoptosis in the brain of mouse models that is medication specific and not necessarily related to the dosages used.⁷ Our case highlights a rare but important adverse event associated with even low-dose cyclosporine use that should be considered in patients currently taking cyclosporine who present with acute neurologic changes.

To the Editor:

Cyclosporine is an immunomodulatory medication that impacts T-lymphocyte function through calcineurin inhibition and suppression of IL-2 expression. Oral cyclosporine at low doses (1–3 mg/kg/d) is one of the more common systemic treatment options for moderate to severe atopic dermatitis. At these doses it has been shown to have therapeutic benefit in several skin conditions, including chronic spontaneous urticaria,¹ psoriasis,² and atopic dermatitis.³ When used at higher doses for conditions such as glomerulonephritis or transplantation, adverse effects may be notable, and close monitoring of drug metabolism as well as end-organ function is required. In contrast, severe adverse effects are uncommon with the lower doses of cyclosporine used for cutaneous conditions, and monitoring serum drug levels is not routinely practiced.⁴

A 58-year-old man was referred to clinic with severe atopic dermatitis refractory to maximal topical therapy prescribed by an outside physician. He was started on cyclosporine as an anticipated bridge to dupilumab biologic therapy. He had no history of hypertension, renal disease, or hepatic insufficiency prior to starting therapy. He demonstrated notable clinical improvement at a cyclosporine dosage of 300 mg/d (equating to 3.7 mg/kg/d). Three months after initiation of therapy, the patient presented to a local emergency department with new-onset seizurelike activity, confusion, and agitation. He was normotensive with clinical concern for status epilepticus. An initial laboratory assessment included a complete blood cell count, serum electrolyte panel, and urine toxicology screen, which were unremarkable. Computed tomography of the head showed confluent white-matter hypodensities in the left parietal-temporal-occipital lobes. Magnetic resonance imaging (MRI) of the brain showed innumerable peripherally distributed foci of microhemorrhage and vasogenic edema within the left parietal-temporal-occipital lobes (Figure).

He was intubated and sedated with admission to the medical intensive care unit, where a random cyclosporine level drawn approximately 9 hours after the prior dose was noted to be 263 ng/mL. Although target therapeutic levels for cyclosporine vary based on indication, toxic supratherapeutic levels generally are considered to be greater than 400 ng/mL.⁵ He had no evidence of acute kidney injury, uremia, or hypertension throughout hospitalization. An electroencephalogram showed left parieto-occipital periodic epileptiform discharges with generalized slowing. Cyclosporine was discontinued, and he was started on levetiracetam. His clinical and neuroimaging findings improved over the course of the 1-week hospitalization without any further intervention. Four weeks after hospitalization, he had full neurologic, electroencephalogram, and imaging recovery. Based on the presenting symptoms, transient neuroimaging findings, and full recovery with discontinuation of cyclosporine, the patient was diagnosed with cyclosporine-induced posterior reversible encephalopathy syndrome (PRES).

The diagnosis of PRES requires evidence of acute neurologic symptoms and radiographic findings of cortical/subcortical white-matter changes on computed tomography or MRI consistent with edema. The pathophysiology is not fully understood but appears to be related to vasogenic edema, primarily impacting the posterior aspect of the brain. There have been many reported offending agents, and symptoms typically resolve following cessation of these medications. Cases of cyclosporine-induced PRES have been reported, but most occurred at higher doses within weeks of medication initiation. Two cases of cyclosporine-induced PRES treated with cutaneous dosing have been reported; neither patient was taking it for atopic dermatitis.⁶

Cyclosporine-induced PRES remains a pathophysiologic conundrum. However, there is evidence to support direct endothelial damage causing cellular apoptosis in the brain of mouse models that is medication specific and not necessarily related to the dosages used.⁷ Our case highlights a rare but important adverse event associated with even low-dose cyclosporine use that should be considered in patients currently taking cyclosporine who present with acute neurologic changes.

To the Editor:

Cyclosporine is an immunomodulatory medication that impacts T-lymphocyte function through calcineurin inhibition and suppression of IL-2 expression. Oral cyclosporine at low doses (1–3 mg/kg/d) is one of the more common systemic treatment options for moderate to severe atopic dermatitis. At these doses it has been shown to have therapeutic benefit in several skin conditions, including chronic spontaneous urticaria,¹ psoriasis,² and atopic dermatitis.³ When used at higher doses for conditions such as glomerulonephritis or transplantation, adverse effects may be notable, and close monitoring of drug metabolism as well as end-organ function is required. In contrast, severe adverse effects are uncommon with the lower doses of cyclosporine used for cutaneous conditions, and monitoring serum drug levels is not routinely practiced.⁴

A 58-year-old man was referred to clinic with severe atopic dermatitis refractory to maximal topical therapy prescribed by an outside physician. He was started on cyclosporine as an anticipated bridge to dupilumab biologic therapy. He had no history of hypertension, renal disease, or hepatic insufficiency prior to starting therapy. He demonstrated notable clinical improvement at a cyclosporine dosage of 300 mg/d (equating to 3.7 mg/kg/d). Three months after initiation of therapy, the patient presented to a local emergency department with new-onset seizurelike activity, confusion, and agitation. He was normotensive with clinical concern for status epilepticus. An initial laboratory assessment included a complete blood cell count, serum electrolyte panel, and urine toxicology screen, which were unremarkable. Computed tomography of the head showed confluent white-matter hypodensities in the left parietal-temporal-occipital lobes. Magnetic resonance imaging (MRI) of the brain showed innumerable peripherally distributed foci of microhemorrhage and vasogenic edema within the left parietal-temporal-occipital lobes (Figure).

He was intubated and sedated with admission to the medical intensive care unit, where a random cyclosporine level drawn approximately 9 hours after the prior dose was noted to be 263 ng/mL. Although target therapeutic levels for cyclosporine vary based on indication, toxic supratherapeutic levels generally are considered to be greater than 400 ng/mL.⁵ He had no evidence of acute kidney injury, uremia, or hypertension throughout hospitalization. An electroencephalogram showed left parieto-occipital periodic epileptiform discharges with generalized slowing. Cyclosporine was discontinued, and he was started on levetiracetam. His clinical and neuroimaging findings improved over the course of the 1-week hospitalization without any further intervention. Four weeks after hospitalization, he had full neurologic, electroencephalogram, and imaging recovery. Based on the presenting symptoms, transient neuroimaging findings, and full recovery with discontinuation of cyclosporine, the patient was diagnosed with cyclosporine-induced posterior reversible encephalopathy syndrome (PRES).

The diagnosis of PRES requires evidence of acute neurologic symptoms and radiographic findings of cortical/subcortical white-matter changes on computed tomography or MRI consistent with edema. The pathophysiology is not fully understood but appears to be related to vasogenic edema, primarily impacting the posterior aspect of the brain. There have been many reported offending agents, and symptoms typically resolve following cessation of these medications. Cases of cyclosporine-induced PRES have been reported, but most occurred at higher doses within weeks of medication initiation. Two cases of cyclosporine-induced PRES treated with cutaneous dosing have been reported; neither patient was taking it for atopic dermatitis.⁶

Cyclosporine-induced PRES remains a pathophysiologic conundrum. However, there is evidence to support direct endothelial damage causing cellular apoptosis in the brain of mouse models that is medication specific and not necessarily related to the dosages used.⁷ Our case highlights a rare but important adverse event associated with even low-dose cyclosporine use that should be considered in patients currently taking cyclosporine who present with acute neurologic changes.

To the Editor:

The recent global mpox (monkeypox) outbreak that started in May 2022 has distinctive risk factors, clinical features, and patient attributes that can portend dissemination of infection. We report a case of Kaposi varicelliform eruption (KVE) over a peeling sunburn after mpox infection. Dermatologists should recognize cutaneous risk factors for dissemination of mpox.

A 35-year-old man who was otherwise healthy presented with a papulopustular eruption that began on the shoulders in an area that had been sunburned 24 to 48 hours earlier. He experienced fever (temperature, 38.6 °C)[101.5 °F]), chills, malaise, and the appearance of a painful penile ulcer. He reported a recent male sexual partner a week prior to the eruption during travel to eastern Asia and a subsequent male partner in the United States 5 days prior to eruption. Physical examination revealed a peeling sunburn with sharp clothing demarcation. Locations with the most notable desquamation—the superior shoulders, dorsal arms, upper chest, and ventral thighs—positively correlated with the highest density of scattered, discrete, erythematous-based pustules and pink papules, some with crusted umbilication (Figures 1 and 2). Lesions spared sun-protected locations except a punctate painful ulcer on the buccal mucosa and a tender well-demarcated ulcer with elevated borders on the ventral penile shaft. HIV antigen/antibody testing was negative; syphilis antibody testing was positive due to a prior infection 1 year earlier with titers down to 1:1. A penile ulcer swab did not detect herpes simplex virus types 1/2 DNA. Pharyngeal, penile, and rectal swabs were negative for chlamydia or gonorrhea DNA. A polymerase chain reaction assay of a pustule was positive for orthopoxvirus, and the Centers for Disease Control and Prevention confirmed Monkeypox virus. On day 12, a penile ulcer biopsy was nonspecific with dense mixed inflammation; immunohistochemical stains for Treponema pallidum and herpes simplex virus types 1/2 were negative. Consideration was given to starting antiviral treatment with tecovirimat, which is approved by the US Food and Drug Administration for smallpox caused by variola virus, through the Centers for Disease Control and Prevention expanded access protocol, but the patient’s symptoms and lesions cleared quickly without intervention. The patient’s recent sexual contact in the United States later tested positive for mpox. Given that the density of our patient’s mpox lesions positively correlated with areas of peeling sunburn with rapid spread during the period of desquamation, he was diagnosed with KVE due to mpox in the setting of a peeling sunburn.

The recent mpox outbreak began in May 2022, and within 3 months there were more than 31,000 confirmed mpox cases worldwide, with more than 11,000 of those cases within the United States across 49 states and Puerto Rico.¹ Gay, bisexual, and other men who have sex with men have constituted the majority of cases. Although prior outbreaks have exhibited cases of classic mpox lesions, the current cases are clinically distinctive from classic mpox due to prevalent orogenital involvement and generalized symptoms that often are mild, nonexistent, or can occur after the cutaneous lesions.²

Although most current cases of mpox have been mildly symptomatic, several patients have been ill enough to require hospital admission, including patients with severe anogenital ulcerative lesions or bacterial superinfection.³ Antiviral treatment with tecovirimat may be warranted for patients with severe disease or those at risk of becoming severe due to immunosuppression, pregnancy/breastfeeding, complications (as determined by the provider), younger age (ie, pediatric patients), or skin barrier disruption. Dermatologists play a particularly important role in identifying cutaneous risk factors that may indicate progression of infection (eg, atopic dermatitis, severe acne, intertrigo, Darier disease). Kaposi varicelliform eruption is the phenomenon where a more typically localized vesicular infection is disseminated to areas with a defective skin barrier.² Eczema herpeticum refers to the most common type of KVE due to herpes simplex virus, but other known etiologies of KVE include coxsackievirus A16, vaccinia virus, varicella-zoster virus, and smallpox.² Although classic mpox previously had only the theoretical potential to lead to a secondary KVE, we expect the literature to evolve as cases spread, with one recent report of eczema monkeypoxicum in the setting of atopic dermatitis.⁴

At the time of publication, mpox cases have notably dropped globally due to public health interventions; however, mpox infections are ongoing in areas previously identified as nonendemic. Given the distinctive risk factors and clinical presentations of this most recent outbreak, clinicians will need to be adept at identifying not only infection but also risk for dissemination, including skin barrier disruption.

To the Editor:

The recent global mpox (monkeypox) outbreak that started in May 2022 has distinctive risk factors, clinical features, and patient attributes that can portend dissemination of infection. We report a case of Kaposi varicelliform eruption (KVE) over a peeling sunburn after mpox infection. Dermatologists should recognize cutaneous risk factors for dissemination of mpox.

A 35-year-old man who was otherwise healthy presented with a papulopustular eruption that began on the shoulders in an area that had been sunburned 24 to 48 hours earlier. He experienced fever (temperature, 38.6 °C)[101.5 °F]), chills, malaise, and the appearance of a painful penile ulcer. He reported a recent male sexual partner a week prior to the eruption during travel to eastern Asia and a subsequent male partner in the United States 5 days prior to eruption. Physical examination revealed a peeling sunburn with sharp clothing demarcation. Locations with the most notable desquamation—the superior shoulders, dorsal arms, upper chest, and ventral thighs—positively correlated with the highest density of scattered, discrete, erythematous-based pustules and pink papules, some with crusted umbilication (Figures 1 and 2). Lesions spared sun-protected locations except a punctate painful ulcer on the buccal mucosa and a tender well-demarcated ulcer with elevated borders on the ventral penile shaft. HIV antigen/antibody testing was negative; syphilis antibody testing was positive due to a prior infection 1 year earlier with titers down to 1:1. A penile ulcer swab did not detect herpes simplex virus types 1/2 DNA. Pharyngeal, penile, and rectal swabs were negative for chlamydia or gonorrhea DNA. A polymerase chain reaction assay of a pustule was positive for orthopoxvirus, and the Centers for Disease Control and Prevention confirmed Monkeypox virus. On day 12, a penile ulcer biopsy was nonspecific with dense mixed inflammation; immunohistochemical stains for Treponema pallidum and herpes simplex virus types 1/2 were negative. Consideration was given to starting antiviral treatment with tecovirimat, which is approved by the US Food and Drug Administration for smallpox caused by variola virus, through the Centers for Disease Control and Prevention expanded access protocol, but the patient’s symptoms and lesions cleared quickly without intervention. The patient’s recent sexual contact in the United States later tested positive for mpox. Given that the density of our patient’s mpox lesions positively correlated with areas of peeling sunburn with rapid spread during the period of desquamation, he was diagnosed with KVE due to mpox in the setting of a peeling sunburn.

The recent mpox outbreak began in May 2022, and within 3 months there were more than 31,000 confirmed mpox cases worldwide, with more than 11,000 of those cases within the United States across 49 states and Puerto Rico.¹ Gay, bisexual, and other men who have sex with men have constituted the majority of cases. Although prior outbreaks have exhibited cases of classic mpox lesions, the current cases are clinically distinctive from classic mpox due to prevalent orogenital involvement and generalized symptoms that often are mild, nonexistent, or can occur after the cutaneous lesions.²

Although most current cases of mpox have been mildly symptomatic, several patients have been ill enough to require hospital admission, including patients with severe anogenital ulcerative lesions or bacterial superinfection.³ Antiviral treatment with tecovirimat may be warranted for patients with severe disease or those at risk of becoming severe due to immunosuppression, pregnancy/breastfeeding, complications (as determined by the provider), younger age (ie, pediatric patients), or skin barrier disruption. Dermatologists play a particularly important role in identifying cutaneous risk factors that may indicate progression of infection (eg, atopic dermatitis, severe acne, intertrigo, Darier disease). Kaposi varicelliform eruption is the phenomenon where a more typically localized vesicular infection is disseminated to areas with a defective skin barrier.² Eczema herpeticum refers to the most common type of KVE due to herpes simplex virus, but other known etiologies of KVE include coxsackievirus A16, vaccinia virus, varicella-zoster virus, and smallpox.² Although classic mpox previously had only the theoretical potential to lead to a secondary KVE, we expect the literature to evolve as cases spread, with one recent report of eczema monkeypoxicum in the setting of atopic dermatitis.⁴

At the time of publication, mpox cases have notably dropped globally due to public health interventions; however, mpox infections are ongoing in areas previously identified as nonendemic. Given the distinctive risk factors and clinical presentations of this most recent outbreak, clinicians will need to be adept at identifying not only infection but also risk for dissemination, including skin barrier disruption.

To the Editor:

The recent global mpox (monkeypox) outbreak that started in May 2022 has distinctive risk factors, clinical features, and patient attributes that can portend dissemination of infection. We report a case of Kaposi varicelliform eruption (KVE) over a peeling sunburn after mpox infection. Dermatologists should recognize cutaneous risk factors for dissemination of mpox.

A 35-year-old man who was otherwise healthy presented with a papulopustular eruption that began on the shoulders in an area that had been sunburned 24 to 48 hours earlier. He experienced fever (temperature, 38.6 °C)[101.5 °F]), chills, malaise, and the appearance of a painful penile ulcer. He reported a recent male sexual partner a week prior to the eruption during travel to eastern Asia and a subsequent male partner in the United States 5 days prior to eruption. Physical examination revealed a peeling sunburn with sharp clothing demarcation. Locations with the most notable desquamation—the superior shoulders, dorsal arms, upper chest, and ventral thighs—positively correlated with the highest density of scattered, discrete, erythematous-based pustules and pink papules, some with crusted umbilication (Figures 1 and 2). Lesions spared sun-protected locations except a punctate painful ulcer on the buccal mucosa and a tender well-demarcated ulcer with elevated borders on the ventral penile shaft. HIV antigen/antibody testing was negative; syphilis antibody testing was positive due to a prior infection 1 year earlier with titers down to 1:1. A penile ulcer swab did not detect herpes simplex virus types 1/2 DNA. Pharyngeal, penile, and rectal swabs were negative for chlamydia or gonorrhea DNA. A polymerase chain reaction assay of a pustule was positive for orthopoxvirus, and the Centers for Disease Control and Prevention confirmed Monkeypox virus. On day 12, a penile ulcer biopsy was nonspecific with dense mixed inflammation; immunohistochemical stains for Treponema pallidum and herpes simplex virus types 1/2 were negative. Consideration was given to starting antiviral treatment with tecovirimat, which is approved by the US Food and Drug Administration for smallpox caused by variola virus, through the Centers for Disease Control and Prevention expanded access protocol, but the patient’s symptoms and lesions cleared quickly without intervention. The patient’s recent sexual contact in the United States later tested positive for mpox. Given that the density of our patient’s mpox lesions positively correlated with areas of peeling sunburn with rapid spread during the period of desquamation, he was diagnosed with KVE due to mpox in the setting of a peeling sunburn.

The recent mpox outbreak began in May 2022, and within 3 months there were more than 31,000 confirmed mpox cases worldwide, with more than 11,000 of those cases within the United States across 49 states and Puerto Rico.¹ Gay, bisexual, and other men who have sex with men have constituted the majority of cases. Although prior outbreaks have exhibited cases of classic mpox lesions, the current cases are clinically distinctive from classic mpox due to prevalent orogenital involvement and generalized symptoms that often are mild, nonexistent, or can occur after the cutaneous lesions.²

Although most current cases of mpox have been mildly symptomatic, several patients have been ill enough to require hospital admission, including patients with severe anogenital ulcerative lesions or bacterial superinfection.³ Antiviral treatment with tecovirimat may be warranted for patients with severe disease or those at risk of becoming severe due to immunosuppression, pregnancy/breastfeeding, complications (as determined by the provider), younger age (ie, pediatric patients), or skin barrier disruption. Dermatologists play a particularly important role in identifying cutaneous risk factors that may indicate progression of infection (eg, atopic dermatitis, severe acne, intertrigo, Darier disease). Kaposi varicelliform eruption is the phenomenon where a more typically localized vesicular infection is disseminated to areas with a defective skin barrier.² Eczema herpeticum refers to the most common type of KVE due to herpes simplex virus, but other known etiologies of KVE include coxsackievirus A16, vaccinia virus, varicella-zoster virus, and smallpox.² Although classic mpox previously had only the theoretical potential to lead to a secondary KVE, we expect the literature to evolve as cases spread, with one recent report of eczema monkeypoxicum in the setting of atopic dermatitis.⁴

At the time of publication, mpox cases have notably dropped globally due to public health interventions; however, mpox infections are ongoing in areas previously identified as nonendemic. Given the distinctive risk factors and clinical presentations of this most recent outbreak, clinicians will need to be adept at identifying not only infection but also risk for dissemination, including skin barrier disruption.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

 

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

 

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

 

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.