Cutis

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.

A biopsy showed a markedly elastotic dermis consisting of a palisading granulomatous inflammatory infiltrate and numerous multinucleated histiocytes (Figure). These histopathologic findings along with the clinical presentation confirmed a diagnosis of annular elastolytic granuloma (AEG). Treatment consisting of 3 months of oral minocycline, 2 months of oral doxycycline, and clobetasol ointment all failed. At that point, oral hydroxychloroquine was recommended. Our patient was lost to follow-up by dermatology, then subsequently was placed on hydroxychloroquine by rheumatology to treat both the osteoarthritis and AEG. A follow-up appointment with dermatology was planned for 3 months to monitor hydroxychloroquine treatment and monitor treatment progress; however, she did not follow-up or seek further treatment.

Annular elastolytic granuloma clinically is similar to granuloma annulare (GA), with both presenting as annular plaques surrounded by an elevated border.¹ Although AEG clinically is distinct with hypopigmented atrophied plaque centers,² a biopsy is required to confirm the lack of elastic tissue in zones of atrophy and the presence of multinucleated histiocytes.^1,3 Lesions most commonly are seen clinically on sun-exposed areas in middle-aged White women; however, they rarely have been seen on frequently covered skin.⁴ Our case illustrates the striking photodistribution of AEG, especially on the posterior neck area. The clinical diagnoses of AEG, annular elastolytic giant cell granuloma, and GA in sun-exposed areas are synonymous and can be used interchangeably.^5,6

Pathologies considered in the diagnosis of AEG include but are not limited to tinea corporis, annular lichen planus, erythema annulare centrifugum, and necrobiosis lipoidica. Scaling typically is absent in AEG, while tinea corporis presents with hyphae within the stratum corneum of the plaques.⁷ Papules along the periphery of annular lesions are more typical of annular lichen planus than AEG, and they tend to have a more purple hue.⁸ Erythema annulare centrifugum has annular erythematous plaques similar to those found in AEG but differs with scaling on the inner margins of these plaques. Histopathology presenting with a lymphocytic infiltrate surrounding vasculature and no indication of elastolytic degradation would further indicate a diagnosis of erythema annulare centrifugum.⁹ Histopathology showing necrobiosis, lipid depositions, and vascular wall thickenings is indicative of necrobiosis lipoidica.¹⁰

Similar to GA,¹¹ the cause of AEG is idiopathic.² Annular elastolytic granuloma and GA differ in the fact that elastin degradation is characteristic of AEG compared to collagen degradation in GA. It is suspected that elastin degradation in AEG patients is caused by an immune response triggering phagocytosis of elastin by multinucleated histiocytes.² Actinic damage also is considered a possible cause of elastin fiber degradation in AEG.¹² Granuloma annulare can be ruled out and the diagnosis of AEG confirmed with the absence of elastin fibers and mucin on pathology.¹³

Although there is no established first-line treatment of AEG, successful treatment has been achieved with antimalarial drugs paired with topical steroids.¹⁴ Treatment recommendations for AEG include minocycline, chloroquine, hydroxychloroquine, tranilast, and oral retinoids, as well as oral and topical steroids. In clinical cases where AEG occurs in the setting of a chronic disease such as diabetes mellitus, vascular occlusion, arthritis, or hypertension, treatment of underlying disease has been shown to resolve AEG symptoms.¹⁴

Although light therapy is not common for AEG, UV light radiation has demonstrated success in treating AEG.^15,16 One study showed complete clearance of granulomatous papules after narrowband UVB treatment.¹⁵ Another study showed that 2 patients treated with psoralen plus UVA therapy reached complete clearance of AEG lasting at least 3 months after treatment.¹⁶

A biopsy showed a markedly elastotic dermis consisting of a palisading granulomatous inflammatory infiltrate and numerous multinucleated histiocytes (Figure). These histopathologic findings along with the clinical presentation confirmed a diagnosis of annular elastolytic granuloma (AEG). Treatment consisting of 3 months of oral minocycline, 2 months of oral doxycycline, and clobetasol ointment all failed. At that point, oral hydroxychloroquine was recommended. Our patient was lost to follow-up by dermatology, then subsequently was placed on hydroxychloroquine by rheumatology to treat both the osteoarthritis and AEG. A follow-up appointment with dermatology was planned for 3 months to monitor hydroxychloroquine treatment and monitor treatment progress; however, she did not follow-up or seek further treatment.

Annular elastolytic granuloma clinically is similar to granuloma annulare (GA), with both presenting as annular plaques surrounded by an elevated border.¹ Although AEG clinically is distinct with hypopigmented atrophied plaque centers,² a biopsy is required to confirm the lack of elastic tissue in zones of atrophy and the presence of multinucleated histiocytes.^1,3 Lesions most commonly are seen clinically on sun-exposed areas in middle-aged White women; however, they rarely have been seen on frequently covered skin.⁴ Our case illustrates the striking photodistribution of AEG, especially on the posterior neck area. The clinical diagnoses of AEG, annular elastolytic giant cell granuloma, and GA in sun-exposed areas are synonymous and can be used interchangeably.^5,6

Pathologies considered in the diagnosis of AEG include but are not limited to tinea corporis, annular lichen planus, erythema annulare centrifugum, and necrobiosis lipoidica. Scaling typically is absent in AEG, while tinea corporis presents with hyphae within the stratum corneum of the plaques.⁷ Papules along the periphery of annular lesions are more typical of annular lichen planus than AEG, and they tend to have a more purple hue.⁸ Erythema annulare centrifugum has annular erythematous plaques similar to those found in AEG but differs with scaling on the inner margins of these plaques. Histopathology presenting with a lymphocytic infiltrate surrounding vasculature and no indication of elastolytic degradation would further indicate a diagnosis of erythema annulare centrifugum.⁹ Histopathology showing necrobiosis, lipid depositions, and vascular wall thickenings is indicative of necrobiosis lipoidica.¹⁰

Similar to GA,¹¹ the cause of AEG is idiopathic.² Annular elastolytic granuloma and GA differ in the fact that elastin degradation is characteristic of AEG compared to collagen degradation in GA. It is suspected that elastin degradation in AEG patients is caused by an immune response triggering phagocytosis of elastin by multinucleated histiocytes.² Actinic damage also is considered a possible cause of elastin fiber degradation in AEG.¹² Granuloma annulare can be ruled out and the diagnosis of AEG confirmed with the absence of elastin fibers and mucin on pathology.¹³

Although there is no established first-line treatment of AEG, successful treatment has been achieved with antimalarial drugs paired with topical steroids.¹⁴ Treatment recommendations for AEG include minocycline, chloroquine, hydroxychloroquine, tranilast, and oral retinoids, as well as oral and topical steroids. In clinical cases where AEG occurs in the setting of a chronic disease such as diabetes mellitus, vascular occlusion, arthritis, or hypertension, treatment of underlying disease has been shown to resolve AEG symptoms.¹⁴

Although light therapy is not common for AEG, UV light radiation has demonstrated success in treating AEG.^15,16 One study showed complete clearance of granulomatous papules after narrowband UVB treatment.¹⁵ Another study showed that 2 patients treated with psoralen plus UVA therapy reached complete clearance of AEG lasting at least 3 months after treatment.¹⁶

A biopsy showed a markedly elastotic dermis consisting of a palisading granulomatous inflammatory infiltrate and numerous multinucleated histiocytes (Figure). These histopathologic findings along with the clinical presentation confirmed a diagnosis of annular elastolytic granuloma (AEG). Treatment consisting of 3 months of oral minocycline, 2 months of oral doxycycline, and clobetasol ointment all failed. At that point, oral hydroxychloroquine was recommended. Our patient was lost to follow-up by dermatology, then subsequently was placed on hydroxychloroquine by rheumatology to treat both the osteoarthritis and AEG. A follow-up appointment with dermatology was planned for 3 months to monitor hydroxychloroquine treatment and monitor treatment progress; however, she did not follow-up or seek further treatment.

Annular elastolytic granuloma clinically is similar to granuloma annulare (GA), with both presenting as annular plaques surrounded by an elevated border.¹ Although AEG clinically is distinct with hypopigmented atrophied plaque centers,² a biopsy is required to confirm the lack of elastic tissue in zones of atrophy and the presence of multinucleated histiocytes.^1,3 Lesions most commonly are seen clinically on sun-exposed areas in middle-aged White women; however, they rarely have been seen on frequently covered skin.⁴ Our case illustrates the striking photodistribution of AEG, especially on the posterior neck area. The clinical diagnoses of AEG, annular elastolytic giant cell granuloma, and GA in sun-exposed areas are synonymous and can be used interchangeably.^5,6

Pathologies considered in the diagnosis of AEG include but are not limited to tinea corporis, annular lichen planus, erythema annulare centrifugum, and necrobiosis lipoidica. Scaling typically is absent in AEG, while tinea corporis presents with hyphae within the stratum corneum of the plaques.⁷ Papules along the periphery of annular lesions are more typical of annular lichen planus than AEG, and they tend to have a more purple hue.⁸ Erythema annulare centrifugum has annular erythematous plaques similar to those found in AEG but differs with scaling on the inner margins of these plaques. Histopathology presenting with a lymphocytic infiltrate surrounding vasculature and no indication of elastolytic degradation would further indicate a diagnosis of erythema annulare centrifugum.⁹ Histopathology showing necrobiosis, lipid depositions, and vascular wall thickenings is indicative of necrobiosis lipoidica.¹⁰

Similar to GA,¹¹ the cause of AEG is idiopathic.² Annular elastolytic granuloma and GA differ in the fact that elastin degradation is characteristic of AEG compared to collagen degradation in GA. It is suspected that elastin degradation in AEG patients is caused by an immune response triggering phagocytosis of elastin by multinucleated histiocytes.² Actinic damage also is considered a possible cause of elastin fiber degradation in AEG.¹² Granuloma annulare can be ruled out and the diagnosis of AEG confirmed with the absence of elastin fibers and mucin on pathology.¹³

Although there is no established first-line treatment of AEG, successful treatment has been achieved with antimalarial drugs paired with topical steroids.¹⁴ Treatment recommendations for AEG include minocycline, chloroquine, hydroxychloroquine, tranilast, and oral retinoids, as well as oral and topical steroids. In clinical cases where AEG occurs in the setting of a chronic disease such as diabetes mellitus, vascular occlusion, arthritis, or hypertension, treatment of underlying disease has been shown to resolve AEG symptoms.¹⁴

Although light therapy is not common for AEG, UV light radiation has demonstrated success in treating AEG.^15,16 One study showed complete clearance of granulomatous papules after narrowband UVB treatment.¹⁵ Another study showed that 2 patients treated with psoralen plus UVA therapy reached complete clearance of AEG lasting at least 3 months after treatment.¹⁶

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.

The Diagnosis: Allergic Contact Dermatitis

This patient’s history and physical examination were most consistent with a diagnosis of allergic contact dermatitis, likely from an additive or diluent solution within the tattoo ink. Her history of a similar transient reaction following tattooing 2 weeks prior lent credence to an allergic etiology. She was treated with triamcinolone cream 0.1% as well as mupirocin ointment 2% for use as both an emollient and for precautionary antimicrobial coverage. The rash resolved within 2 days, and she reported no recurrence at a 6-month follow-up. The cosmesis of her tattoo was preserved.

Acute cellulitis may follow tattooing, but the absence of warmth, pain, or purulence on physical examination made this diagnosis less likely in this patient. Sarcoidosis or other granulomatous reactions may present as papules or nodules arising within a tattoo but would be unlikely to occur the next day. Nontuberculous mycobacterial infection likewise tends to present subacutely or chronically rather than immediately following tattoo application.

Tattooing has existed for millennia and is becoming increasingly popular.^1,2 The tattooing process entails introduction of insoluble pigment compounds into the dermis to create a permanent design on the skin, which most often is accomplished via needling. As a result, tattooed skin is susceptible to both acute and chronic complications. Acute complications prominently include allergic hypersensitivity reactions and pyogenic bacterial infections. Chronic granulomatous, inflammatory, or infectious complications also can occur.

Allergic eczematous reactions to tattooing are well documented in the literature and are thought to originate from sensitization to pigment molecules themselves or alternatively to ink diluent compounds.³ Although reactions to ink diluent chemicals typically are self-resolving, allergic reactions to pigment can persist beyond the acute phase, as these insoluble compounds intentionally remain embedded in the dermis. The mechanism of action may involve haptenization of pigment molecules that then induces allergic hypersensitivity.^3,4 Black pigment typically is derived from carbon black (ie, amorphous combustion byproducts such as soot). Colored inks historically consisted of inorganic heavy metal–containing salts prior to the modern introduction of synthetic azo and polycyclic dyes. These newer colored pigments appear to be less allergenic than their metallic predecessors; however, epidemiologic studies have suggested that allergic reactions still occur more commonly in colored tattoos than black tattoos.¹ Overall, these reactions may occur in as many as one-third of individuals who receive tattoos.^2,4

As with any process that disrupts skin integrity, tattooing carries a risk for transmitting various infectious pathogens. Microbes may originate from adjacent skin, contaminated needles, ink bottles, or nonsterile ink diluents. Although tattoo parlors and artists may undergo licensing to demonstrate adherence to hygienic standards, regulations vary between states and do not include testing of ink or ink additives to ensure sterility.^4,5 Staphylococci and streptococci commonly are implicated in acute pyogenic skin infections following tattooing.^5,6 Nontuberculous mycobacteria increasingly are being recognized as causative organisms for granulomatous lesions developing subacutely or even months after receiving a new tattoo.^5,7 Local and systemic viral infections also may be transmitted during tattooing; cases of tattoo-transmitted viral warts, molluscum contagiosum, and hepatitis B and C viruses all have been observed.^5,6,8 Herpes simplex virus transmission (colloquially termed herpes compunctorum) and HIV transmission through tattooing also are hypothesized to be possible, though there is a paucity of known cases for each.^8,9

Chronic inflammatory, granulomatous, or neoplastic lesions may arise within tattooed skin months or years after tattooing. Foreign body granulomas, sarcoidosis, pseudolymphoma, pseudoepitheliomatous hyperplasia, and keratoacanthoma are some representative entities.^3,5 Cases of cancerous lesions in tattooed skin have been documented, but their incidence appears similar to nontattooed skin.³ These broad categories of lesions are clinically diverse but may be difficult to definitively diagnose on examination alone; therefore, a biopsy should be strongly considered for any subacute to chronic skin lesions within a tattoo. Patients may be hesitant to disrupt the cosmesis of a tattoo but should be counseled on the attendant risks and benefits to make an informed decision regarding biopsy.

The Diagnosis: Allergic Contact Dermatitis

This patient’s history and physical examination were most consistent with a diagnosis of allergic contact dermatitis, likely from an additive or diluent solution within the tattoo ink. Her history of a similar transient reaction following tattooing 2 weeks prior lent credence to an allergic etiology. She was treated with triamcinolone cream 0.1% as well as mupirocin ointment 2% for use as both an emollient and for precautionary antimicrobial coverage. The rash resolved within 2 days, and she reported no recurrence at a 6-month follow-up. The cosmesis of her tattoo was preserved.

Acute cellulitis may follow tattooing, but the absence of warmth, pain, or purulence on physical examination made this diagnosis less likely in this patient. Sarcoidosis or other granulomatous reactions may present as papules or nodules arising within a tattoo but would be unlikely to occur the next day. Nontuberculous mycobacterial infection likewise tends to present subacutely or chronically rather than immediately following tattoo application.

Tattooing has existed for millennia and is becoming increasingly popular.^1,2 The tattooing process entails introduction of insoluble pigment compounds into the dermis to create a permanent design on the skin, which most often is accomplished via needling. As a result, tattooed skin is susceptible to both acute and chronic complications. Acute complications prominently include allergic hypersensitivity reactions and pyogenic bacterial infections. Chronic granulomatous, inflammatory, or infectious complications also can occur.

Allergic eczematous reactions to tattooing are well documented in the literature and are thought to originate from sensitization to pigment molecules themselves or alternatively to ink diluent compounds.³ Although reactions to ink diluent chemicals typically are self-resolving, allergic reactions to pigment can persist beyond the acute phase, as these insoluble compounds intentionally remain embedded in the dermis. The mechanism of action may involve haptenization of pigment molecules that then induces allergic hypersensitivity.^3,4 Black pigment typically is derived from carbon black (ie, amorphous combustion byproducts such as soot). Colored inks historically consisted of inorganic heavy metal–containing salts prior to the modern introduction of synthetic azo and polycyclic dyes. These newer colored pigments appear to be less allergenic than their metallic predecessors; however, epidemiologic studies have suggested that allergic reactions still occur more commonly in colored tattoos than black tattoos.¹ Overall, these reactions may occur in as many as one-third of individuals who receive tattoos.^2,4

As with any process that disrupts skin integrity, tattooing carries a risk for transmitting various infectious pathogens. Microbes may originate from adjacent skin, contaminated needles, ink bottles, or nonsterile ink diluents. Although tattoo parlors and artists may undergo licensing to demonstrate adherence to hygienic standards, regulations vary between states and do not include testing of ink or ink additives to ensure sterility.^4,5 Staphylococci and streptococci commonly are implicated in acute pyogenic skin infections following tattooing.^5,6 Nontuberculous mycobacteria increasingly are being recognized as causative organisms for granulomatous lesions developing subacutely or even months after receiving a new tattoo.^5,7 Local and systemic viral infections also may be transmitted during tattooing; cases of tattoo-transmitted viral warts, molluscum contagiosum, and hepatitis B and C viruses all have been observed.^5,6,8 Herpes simplex virus transmission (colloquially termed herpes compunctorum) and HIV transmission through tattooing also are hypothesized to be possible, though there is a paucity of known cases for each.^8,9

Chronic inflammatory, granulomatous, or neoplastic lesions may arise within tattooed skin months or years after tattooing. Foreign body granulomas, sarcoidosis, pseudolymphoma, pseudoepitheliomatous hyperplasia, and keratoacanthoma are some representative entities.^3,5 Cases of cancerous lesions in tattooed skin have been documented, but their incidence appears similar to nontattooed skin.³ These broad categories of lesions are clinically diverse but may be difficult to definitively diagnose on examination alone; therefore, a biopsy should be strongly considered for any subacute to chronic skin lesions within a tattoo. Patients may be hesitant to disrupt the cosmesis of a tattoo but should be counseled on the attendant risks and benefits to make an informed decision regarding biopsy.

The Diagnosis: Allergic Contact Dermatitis

This patient’s history and physical examination were most consistent with a diagnosis of allergic contact dermatitis, likely from an additive or diluent solution within the tattoo ink. Her history of a similar transient reaction following tattooing 2 weeks prior lent credence to an allergic etiology. She was treated with triamcinolone cream 0.1% as well as mupirocin ointment 2% for use as both an emollient and for precautionary antimicrobial coverage. The rash resolved within 2 days, and she reported no recurrence at a 6-month follow-up. The cosmesis of her tattoo was preserved.

Acute cellulitis may follow tattooing, but the absence of warmth, pain, or purulence on physical examination made this diagnosis less likely in this patient. Sarcoidosis or other granulomatous reactions may present as papules or nodules arising within a tattoo but would be unlikely to occur the next day. Nontuberculous mycobacterial infection likewise tends to present subacutely or chronically rather than immediately following tattoo application.

Tattooing has existed for millennia and is becoming increasingly popular.^1,2 The tattooing process entails introduction of insoluble pigment compounds into the dermis to create a permanent design on the skin, which most often is accomplished via needling. As a result, tattooed skin is susceptible to both acute and chronic complications. Acute complications prominently include allergic hypersensitivity reactions and pyogenic bacterial infections. Chronic granulomatous, inflammatory, or infectious complications also can occur.

Allergic eczematous reactions to tattooing are well documented in the literature and are thought to originate from sensitization to pigment molecules themselves or alternatively to ink diluent compounds.³ Although reactions to ink diluent chemicals typically are self-resolving, allergic reactions to pigment can persist beyond the acute phase, as these insoluble compounds intentionally remain embedded in the dermis. The mechanism of action may involve haptenization of pigment molecules that then induces allergic hypersensitivity.^3,4 Black pigment typically is derived from carbon black (ie, amorphous combustion byproducts such as soot). Colored inks historically consisted of inorganic heavy metal–containing salts prior to the modern introduction of synthetic azo and polycyclic dyes. These newer colored pigments appear to be less allergenic than their metallic predecessors; however, epidemiologic studies have suggested that allergic reactions still occur more commonly in colored tattoos than black tattoos.¹ Overall, these reactions may occur in as many as one-third of individuals who receive tattoos.^2,4

As with any process that disrupts skin integrity, tattooing carries a risk for transmitting various infectious pathogens. Microbes may originate from adjacent skin, contaminated needles, ink bottles, or nonsterile ink diluents. Although tattoo parlors and artists may undergo licensing to demonstrate adherence to hygienic standards, regulations vary between states and do not include testing of ink or ink additives to ensure sterility.^4,5 Staphylococci and streptococci commonly are implicated in acute pyogenic skin infections following tattooing.^5,6 Nontuberculous mycobacteria increasingly are being recognized as causative organisms for granulomatous lesions developing subacutely or even months after receiving a new tattoo.^5,7 Local and systemic viral infections also may be transmitted during tattooing; cases of tattoo-transmitted viral warts, molluscum contagiosum, and hepatitis B and C viruses all have been observed.^5,6,8 Herpes simplex virus transmission (colloquially termed herpes compunctorum) and HIV transmission through tattooing also are hypothesized to be possible, though there is a paucity of known cases for each.^8,9

Chronic inflammatory, granulomatous, or neoplastic lesions may arise within tattooed skin months or years after tattooing. Foreign body granulomas, sarcoidosis, pseudolymphoma, pseudoepitheliomatous hyperplasia, and keratoacanthoma are some representative entities.^3,5 Cases of cancerous lesions in tattooed skin have been documented, but their incidence appears similar to nontattooed skin.³ These broad categories of lesions are clinically diverse but may be difficult to definitively diagnose on examination alone; therefore, a biopsy should be strongly considered for any subacute to chronic skin lesions within a tattoo. Patients may be hesitant to disrupt the cosmesis of a tattoo but should be counseled on the attendant risks and benefits to make an informed decision regarding biopsy.

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 (645μg/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 (645μg/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 (645μg/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.

The Diagnosis: Darier Disease

A clinical diagnosis of Darier disease was made from the skin findings of pruritic, malodorous, keratotic papules in a seborrheic distribution and pathognomonic nail dystrophy, along with a family history that demonstrated autosomal-dominant inheritance. The ulcerations were suspected to be caused by a superimposed herpes simplex virus (HSV) infection in the form of eczema herpeticum. The clinical diagnosis was later confirmed via punch biopsy. Pathology results demonstrated focal acantholytic dyskeratosis, which was consistent with Darier disease given the focal nature and lack of acanthosis. The patient’s father and sister also were confirmed to have Darier disease by an outside dermatologist.

Darier disease is a rare keratinizing autosomaldominant genodermatosis that occurs due to a mutation in the ATP2A2 gene, which encodes a sarco/endoplasmic reticulum calcium ATPase pump that decreases cell adhesion between keratinocytes, leading to epidermal acantholysis and dyskeratosis and ultimately a disrupted skin barrier.^1,2 Darier disease often presents in childhood and adolescence with papules in a seborrheic distribution on the central chest and back (Figure, A); the intertriginous folds also may be involved. Darier disease can manifest with palmoplantar pits (Figure, B), a cobblestonelike texture of the oral mucosa, acrokeratosis verruciformis of Hopf, and nail findings with alternating red and white longitudinal streaks in the nail bed resembling a candy cane along with characteristic V nicking deformities of the nails themselves (Figure, C). Chronic flares may occur throughout one’s lifetime, with patients experiencing more symptoms in the summer months due to heat, sweat, and UV light exposure, as well as infections that irritate the skin and worsen dyskeratosis. Studies have revealed an association between Darier disease and neuropsychiatric conditions, including major depressive disorder, schizophrenia, and bipolar disorder.^3,4

The skin barrier is compromised in patients with Darier disease, thereby making secondary infection more likely to occur. Polymerase chain reaction swabs of our patient’s purulent ulcerations were positive for HSV type 1, further strengthening a diagnosis of secondary eczema herpeticum, which occurs when patients have widespread HSV superinfecting pre-existing skin conditions such as atopic dermatitis, Darier disease, and Hailey-Hailey disease.^5-7 The lesions are characterized by a monomorphic eruption of umbilicated vesicles on an erythematous base. Lesions can progress to punched-out ulcers and erosions with hemorrhagic crusts that coalesce, forming scalloped borders, similar to our patient’s presentation.⁸

Hailey-Hailey disease, a genodermatosis that alters calcium signaling with an autosomal-dominant inheritance pattern, was unlikely in our patient due to the presence of nail abnormalities and palmar pits that are characteristic of Darier disease. From a purely histopathologic standpoint, Grover disease was considered with skin biopsy demonstrating acantholytic dyskeratosis but was not compatible with the clinical context. Furthermore, trials of antibiotics with group A Streptococcus and Staphylococcus aureus coverage failed in our patient, and she lacked systemic symptoms that would be supportive of a cellulitis diagnosis. The punched-out lesions suggested that an isolated exacerbation of atopic dermatitis was not sufficient to explain all of the clinical findings.

Eczema herpeticum must be considered in the differential diagnosis for patients with underlying Darier disease and widespread ulcerations. Our patient had more recent punched-out ulcerations in the intertriginous regions, with other areas showing later stages of confluent ulcers with scalloped borders. Delayed diagnosis and treatment of eczema herpeticum combined with severe Darier disease can lead to increased risk for hospitalization and rarely fatality.^8,9

Our patient was started on intravenous acyclovir until the lesions crusted and then was transitioned to a suppressive dose of oral valacyclovir given the widespread distribution. The Darier disease itself was managed with topical steroids and a zinc oxide barrier, serving as protectants to pathogens through microscopic breaks in the skin. Our patient also had a mild case of candidal intertrigo that was exacerbated by obesity and managed with topical ketoconazole. Gabapentin, hydromorphone, and acetaminophen were used for pain. She was discharged 10 days after admission with substantial improvement of both the HSV lesions and the irritation from her Darier disease. At follow-up visits 20 days later and again 6 months after discharge, she had been feeling well without any HSV flares.

The eczema herpeticum likely arose from our patient’s chronic skin barrier impairment attributed to Darier disease, leading to the cutaneous inoculation of HSV. Our patient and her family members had never been evaluated by a dermatologist until late in life during this hospitalization. Medication compliance with a suppressive dose of oral valacyclovir and topical steroids is vital to prevent flares of both eczema herpeticum and Darier disease, respectively. This case highlights the importance of dermatology consultation for complex cutaneous findings, as delayed diagnosis and treatment can lead to increased morbidity and mortality.

The Diagnosis: Darier Disease

A clinical diagnosis of Darier disease was made from the skin findings of pruritic, malodorous, keratotic papules in a seborrheic distribution and pathognomonic nail dystrophy, along with a family history that demonstrated autosomal-dominant inheritance. The ulcerations were suspected to be caused by a superimposed herpes simplex virus (HSV) infection in the form of eczema herpeticum. The clinical diagnosis was later confirmed via punch biopsy. Pathology results demonstrated focal acantholytic dyskeratosis, which was consistent with Darier disease given the focal nature and lack of acanthosis. The patient’s father and sister also were confirmed to have Darier disease by an outside dermatologist.

Darier disease is a rare keratinizing autosomaldominant genodermatosis that occurs due to a mutation in the ATP2A2 gene, which encodes a sarco/endoplasmic reticulum calcium ATPase pump that decreases cell adhesion between keratinocytes, leading to epidermal acantholysis and dyskeratosis and ultimately a disrupted skin barrier.^1,2 Darier disease often presents in childhood and adolescence with papules in a seborrheic distribution on the central chest and back (Figure, A); the intertriginous folds also may be involved. Darier disease can manifest with palmoplantar pits (Figure, B), a cobblestonelike texture of the oral mucosa, acrokeratosis verruciformis of Hopf, and nail findings with alternating red and white longitudinal streaks in the nail bed resembling a candy cane along with characteristic V nicking deformities of the nails themselves (Figure, C). Chronic flares may occur throughout one’s lifetime, with patients experiencing more symptoms in the summer months due to heat, sweat, and UV light exposure, as well as infections that irritate the skin and worsen dyskeratosis. Studies have revealed an association between Darier disease and neuropsychiatric conditions, including major depressive disorder, schizophrenia, and bipolar disorder.^3,4

The skin barrier is compromised in patients with Darier disease, thereby making secondary infection more likely to occur. Polymerase chain reaction swabs of our patient’s purulent ulcerations were positive for HSV type 1, further strengthening a diagnosis of secondary eczema herpeticum, which occurs when patients have widespread HSV superinfecting pre-existing skin conditions such as atopic dermatitis, Darier disease, and Hailey-Hailey disease.^5-7 The lesions are characterized by a monomorphic eruption of umbilicated vesicles on an erythematous base. Lesions can progress to punched-out ulcers and erosions with hemorrhagic crusts that coalesce, forming scalloped borders, similar to our patient’s presentation.⁸

Hailey-Hailey disease, a genodermatosis that alters calcium signaling with an autosomal-dominant inheritance pattern, was unlikely in our patient due to the presence of nail abnormalities and palmar pits that are characteristic of Darier disease. From a purely histopathologic standpoint, Grover disease was considered with skin biopsy demonstrating acantholytic dyskeratosis but was not compatible with the clinical context. Furthermore, trials of antibiotics with group A Streptococcus and Staphylococcus aureus coverage failed in our patient, and she lacked systemic symptoms that would be supportive of a cellulitis diagnosis. The punched-out lesions suggested that an isolated exacerbation of atopic dermatitis was not sufficient to explain all of the clinical findings.

Eczema herpeticum must be considered in the differential diagnosis for patients with underlying Darier disease and widespread ulcerations. Our patient had more recent punched-out ulcerations in the intertriginous regions, with other areas showing later stages of confluent ulcers with scalloped borders. Delayed diagnosis and treatment of eczema herpeticum combined with severe Darier disease can lead to increased risk for hospitalization and rarely fatality.^8,9

Our patient was started on intravenous acyclovir until the lesions crusted and then was transitioned to a suppressive dose of oral valacyclovir given the widespread distribution. The Darier disease itself was managed with topical steroids and a zinc oxide barrier, serving as protectants to pathogens through microscopic breaks in the skin. Our patient also had a mild case of candidal intertrigo that was exacerbated by obesity and managed with topical ketoconazole. Gabapentin, hydromorphone, and acetaminophen were used for pain. She was discharged 10 days after admission with substantial improvement of both the HSV lesions and the irritation from her Darier disease. At follow-up visits 20 days later and again 6 months after discharge, she had been feeling well without any HSV flares.

The eczema herpeticum likely arose from our patient’s chronic skin barrier impairment attributed to Darier disease, leading to the cutaneous inoculation of HSV. Our patient and her family members had never been evaluated by a dermatologist until late in life during this hospitalization. Medication compliance with a suppressive dose of oral valacyclovir and topical steroids is vital to prevent flares of both eczema herpeticum and Darier disease, respectively. This case highlights the importance of dermatology consultation for complex cutaneous findings, as delayed diagnosis and treatment can lead to increased morbidity and mortality.

The Diagnosis: Darier Disease

A clinical diagnosis of Darier disease was made from the skin findings of pruritic, malodorous, keratotic papules in a seborrheic distribution and pathognomonic nail dystrophy, along with a family history that demonstrated autosomal-dominant inheritance. The ulcerations were suspected to be caused by a superimposed herpes simplex virus (HSV) infection in the form of eczema herpeticum. The clinical diagnosis was later confirmed via punch biopsy. Pathology results demonstrated focal acantholytic dyskeratosis, which was consistent with Darier disease given the focal nature and lack of acanthosis. The patient’s father and sister also were confirmed to have Darier disease by an outside dermatologist.

Darier disease is a rare keratinizing autosomaldominant genodermatosis that occurs due to a mutation in the ATP2A2 gene, which encodes a sarco/endoplasmic reticulum calcium ATPase pump that decreases cell adhesion between keratinocytes, leading to epidermal acantholysis and dyskeratosis and ultimately a disrupted skin barrier.^1,2 Darier disease often presents in childhood and adolescence with papules in a seborrheic distribution on the central chest and back (Figure, A); the intertriginous folds also may be involved. Darier disease can manifest with palmoplantar pits (Figure, B), a cobblestonelike texture of the oral mucosa, acrokeratosis verruciformis of Hopf, and nail findings with alternating red and white longitudinal streaks in the nail bed resembling a candy cane along with characteristic V nicking deformities of the nails themselves (Figure, C). Chronic flares may occur throughout one’s lifetime, with patients experiencing more symptoms in the summer months due to heat, sweat, and UV light exposure, as well as infections that irritate the skin and worsen dyskeratosis. Studies have revealed an association between Darier disease and neuropsychiatric conditions, including major depressive disorder, schizophrenia, and bipolar disorder.^3,4

The skin barrier is compromised in patients with Darier disease, thereby making secondary infection more likely to occur. Polymerase chain reaction swabs of our patient’s purulent ulcerations were positive for HSV type 1, further strengthening a diagnosis of secondary eczema herpeticum, which occurs when patients have widespread HSV superinfecting pre-existing skin conditions such as atopic dermatitis, Darier disease, and Hailey-Hailey disease.^5-7 The lesions are characterized by a monomorphic eruption of umbilicated vesicles on an erythematous base. Lesions can progress to punched-out ulcers and erosions with hemorrhagic crusts that coalesce, forming scalloped borders, similar to our patient’s presentation.⁸

Hailey-Hailey disease, a genodermatosis that alters calcium signaling with an autosomal-dominant inheritance pattern, was unlikely in our patient due to the presence of nail abnormalities and palmar pits that are characteristic of Darier disease. From a purely histopathologic standpoint, Grover disease was considered with skin biopsy demonstrating acantholytic dyskeratosis but was not compatible with the clinical context. Furthermore, trials of antibiotics with group A Streptococcus and Staphylococcus aureus coverage failed in our patient, and she lacked systemic symptoms that would be supportive of a cellulitis diagnosis. The punched-out lesions suggested that an isolated exacerbation of atopic dermatitis was not sufficient to explain all of the clinical findings.

Eczema herpeticum must be considered in the differential diagnosis for patients with underlying Darier disease and widespread ulcerations. Our patient had more recent punched-out ulcerations in the intertriginous regions, with other areas showing later stages of confluent ulcers with scalloped borders. Delayed diagnosis and treatment of eczema herpeticum combined with severe Darier disease can lead to increased risk for hospitalization and rarely fatality.^8,9

Our patient was started on intravenous acyclovir until the lesions crusted and then was transitioned to a suppressive dose of oral valacyclovir given the widespread distribution. The Darier disease itself was managed with topical steroids and a zinc oxide barrier, serving as protectants to pathogens through microscopic breaks in the skin. Our patient also had a mild case of candidal intertrigo that was exacerbated by obesity and managed with topical ketoconazole. Gabapentin, hydromorphone, and acetaminophen were used for pain. She was discharged 10 days after admission with substantial improvement of both the HSV lesions and the irritation from her Darier disease. At follow-up visits 20 days later and again 6 months after discharge, she had been feeling well without any HSV flares.

The eczema herpeticum likely arose from our patient’s chronic skin barrier impairment attributed to Darier disease, leading to the cutaneous inoculation of HSV. Our patient and her family members had never been evaluated by a dermatologist until late in life during this hospitalization. Medication compliance with a suppressive dose of oral valacyclovir and topical steroids is vital to prevent flares of both eczema herpeticum and Darier disease, respectively. This case highlights the importance of dermatology consultation for complex cutaneous findings, as delayed diagnosis and treatment can lead to increased morbidity and mortality.

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.

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.

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.