Case Letter

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is an uncommon microangiopathy that presents with progressive telangiectases on the lower extremities that can eventually spread to involve the upper extremities and trunk. Systemic involvement is uncommon. The diagnosis is confirmed by biopsy, which demonstrates dilated capillaries and postcapillary venules with eosinophilic hyalinized walls. Treatment generally has focused on the use of vascular lasers.¹ We report a patient with advanced CCV and ocular involvement that responded to a combination of pulsed dye laser (PDL) therapy and sclerotherapy for cutaneous lesions.

A 63-year-old woman presented with partially blanchable, purple-black patches on the lower extremities (Figure 1). The upper extremities had minimal involvement at the time of presentation. A medical history revealed the lesions presented on the legs 10 years prior but were beginning to form on the arms. She had a history of hypertension and bleeding in the retina.

Histopathology revealed prominent dilation of postcapillary venules with eosinophilic collagenous materials in the vessel walls that was positive on periodic acid–Schiff stain, confirming the diagnosis of CCV. The perivascular collagenous material failed to stain with Congo red. Laboratory testing for serum protein electrophoresis, antinuclear antibodies, and baseline hematologic and metabolic panels revealed no abnormalities.

Over 3 years of treatment with PDL, most of the black patches resolved, but prominent telangiectatic vessels remained (Figure 2). Sclerotherapy with polidocanol (10 mg/mL) resulted in clearance of the majority of telangiectatic vessels. After each sclerotherapy treatment, Unna boots were applied for a minimum of 24 hours. The patient had no adverse effects from either PDL or sclerotherapy and was pleased with the results (Figure 3). An ophthalmologist had attributed the retinal bleeding to central serous chorioretinopathy, but tortuosity of superficial scleral and episcleral vessels progressed, suggesting CCV as the more likely cause (Figure 4). Currently, she is being followed for visual changes and further retinal bleeding.

Early CCV typically appears as blanchable pink or red macules, telangiectases, or petechiae on the lower extremities, progressing to involve the trunk and upper extremity.^1-3 In rare cases, CCV presents in a papular or annular variant instead of the typical telangiectatic form.^4,5 As the lesions progress, they often darken in appearance. Bleeding can occur, and the progressive patches are disfiguring.^6,7 Middle-aged to older adults typically present with CCV (range, 16–83 years), with a mean age of 62 years.^1,2,6 This disease affects both males and females, predominantly in White individuals.¹ Extracutaneous manifestations are rare.^1,2,6 One case of mucosal involvement was described in a patient with glossitis and oral erosions.⁸ We found no prior reports of nail or eye changes.^1,2

The etiology of CCV is unknown, but different theories have been proposed. One is that CCV is due to a genetic defect that changes collagen synthesis in the cutaneous microvasculature. Another more widely held belief is that CCV originates from an injury that occurs to the microvasculature endothelial cells. Regardless of the cause of the triggering injury, the result is induced intravascular occlusive microthrombi that cause perivascular fibrosis and endothelial hyperplasia.^2,6,7,9

Cutaneous collagenous vasculopathy may be influenced by systemic diseases. The most common comorbidities are hypertension, cardiovascular disease, diabetes mellitus, and hyperlipidemia.^1,3,6-8 The presentation of CCV with a malignancy is rare; 1 patient was diagnosed with multiple myeloma 18 months after CCV, and another patient’s cutaneous presentation led to discovery of pancreatic cancer with metastasis.^8,10 In this setting, the increased growth factors or hypercoagulability of malignancy may play a role in endothelial cell damage and hyperplasia. Autoimmune vascular injury also has been suggested to trigger CCV; 1 case involved antiribonucleoprotein antibodies, while another case involved anti–endothelial cell antibody assays.¹¹ In addition, CCV has been reported in hypercoagulable patients, demonstrating another route for endothelial damage, with 1 patient being heterozygous for prothrombin G20210A, a report of CCV in a patient with cryofibrinogenemia, and another patient being found positive for lupus anticoagulant.^11,12 Drugs also have been thought to influence CCV, including corticosteroids, lithium, thiothixene, interferon, isotretinoin, calcium channel blockers, antibiotics, hydroxyurea, and antidepressants.^7,11

The diagnosis of CCV is confirmed using light microscopy and collagen-specific immunostaining. Examination shows hyaline eosinophilic deposition of type IV collagen around the affected vessels, with the postcapillary venules showing characteristic duplication of the basal lamina.^3,9 The material stains positive with periodic acid-Schiff and Masson trichrome.³

Underreporting may contribute to the low incidence of CCV. The clinical presentation of CCV is similar to generalized essential telangiectasia, with biopsy distinguishing the two. Other diagnoses in the differential include hereditary hemorrhagic telangiectasia, which typically would have mucosal involvement; radiating telangiectatic mats and a strong family history; and hereditary benign telangiectasia, which typically presents in younger patients aged 1 year to adolescence.¹

Treatment with vascular lasers has been the main focus, using either the 595-nm PDL or the 1064-nm Nd:YAG laser.^6,13 Pulsed dye laser or intense pulsed light devices can improve patient well-being^1,2; intense pulsed light allows for a larger spot size and may be preferred in patients with a larger body surface area involved.¹³ However, a few other treatments have been proposed. One case report noted poor response to sclerotherapy.¹ In another case, a patient treated with a chemotherapy agent, bortezomib, for their concurrent multiple myeloma showed notable CCV cutaneous improvement. The proposed mechanism for bortezomib improving CCV is through its antiproliferative effect on endothelial cells of the superficial dermal vessels.⁸ Our patient did not achieve an adequate response with PDL, but the addition of sclerotherapy with polidocanol induced a successful response.

Patients should be examined for evidence of ocular involvement and referred to an ophthalmologist for appropriate care. Although there is no definite association with systemic illnesses or mediation, recent associations with an autoimmune disorder or underlying malignancy have been noted.^8,10,11 Age-appropriate cancer screening and attention to associated signs and symptoms are recommended.

To the Editor:

Plaquelike or plaque-type syringoma is a lesser-known variant of syringoma that can appear histologically indistinguishable from the superficial portion of microcystic adnexal carcinoma (MAC). The plaquelike variant of syringoma holds a benign clinical course, and no treatment is necessary. Microcystic adnexal carcinoma is distinguished from plaquelike syringoma by an aggressive growth pattern with a high risk for local invasion and recurrence if inadequately treated. Thus, treatment with Mohs micrographic surgery (MMS) has been recommended as the mainstay for MAC. If superficial biopsy specimens reveal suspicion for MAC and patients are referred for MMS, careful consideration should be made to differentiate MAC and plaquelike syringoma early to prevent unnecessary morbidity.

A 78-year-old woman was referred for MMS for a left forehead lesion that was diagnosed via shave biopsy as a desmoplastic and cystic adnexal neoplasm with suspicion for desmoplastic trichoepithelioma or MAC (Figure 1). Upon presentation for MMS, a well-healed, 1.0×0.9-cm scar at the biopsy site on the left forehead was observed (Figure 2A). One stage was obtained by standard MMS technique and sent for intraoperative processing (Figure 2B). Frozen section examination of the first stage demonstrated peripheral margin involvement with syringomatous change confined to the superficial and mid dermis (Figure 3). Before proceeding further, these findings were reviewed with an in-house dermatopathologist, and it was determined that no infiltrative tumor, perineural involvement, or other features to indicate malignancy were noted. A decision was made to refrain from obtaining any additional layers and to send excised Burow triangles for permanent section analysis. A primary linear closure was performed without complication, and the patient was discharged from the ambulatory surgery suite. Histopathologic examination of the Burow triangles later confirmed findings consistent with plaquelike syringoma with no evidence of malignancy (Figure 4).

Syringomas present as small flesh-colored papules in the periorbital areas. These benign neoplasms previously have been classified into 4 major clinical variants: localized, generalized, Down syndrome associated, and familial.¹ The lesser-known plaquelike variant of syringoma was first described by Kikuchi et al² in 1979. Aside from our report, a PubMed search of articles indexed for MEDLINE using the terms plaquelike or plaque-type syringoma yielded 16 cases in the literature.^2-14 Of these, 6 were referred to or encountered in the MMS setting.^8,9,11,12,14 Plaquelike syringoma can be solitary or multiple in presentation.⁶ It most commonly involves the head and neck but also can present on the trunk, arms, legs, and groin areas. The clinical size of plaquelike syringoma is variable, with the largest reported cases extending several centimeters in diameter.^2,6 Similar to reported associations with conventional syringoma, the plaquelike subtype of syringoma has been reported in association with Down syndrome.¹³

Histopathologically, plaquelike syringoma shares features with MAC as well as desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma. Plaquelike syringoma demonstrates broad proliferations of small tubules morphologically reminiscent of tadpoles confined within the dermis. Ducts typically are lined with 2 or 3 layers of small cuboidal cells. Microcystic adnexal carcinoma typically features asymmetric ductal structures lined with single cells extending from the dermis into the subcutis and even underlying muscle, cartilage, or bone.⁸ There are no reliable immunohistochemical stains to differentiate between these 2 entities; thus, the primary distinction lies in the depth of involvement. Desmoplastic trichoepithelioma is composed of narrow cords and nests of basaloid cells of follicular origin commonly admixed with small cornifying cysts appearing in the dermis.⁸ Colonizing Merkel cells positive for cytokeratin 20 often are present in desmoplastic trichoepithelioma and not in syringoma or MAC.¹⁵ Desmoplastic basal cell carcinoma demonstrates narrow strands of basaloid cells of follicular origin appearing in the dermis. Desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma are each fundamentally differentiated from plaquelike syringoma in that proliferations of cords and nests are not of eccrine or apocrine origin.

Several cases of plaquelike syringoma have been challenging to distinguish from MAC in performing MMS.^8,9,11 Underlying extension of this syringoma variant can be far-reaching, extending to several centimeters in size and involving multiple cosmetic subunits.^6,11,14 Inadvertent overtreatment with multiple MMS stages can be avoided with careful recognition of the differentiating histopathologic features. Syringomatous lesions commonly are encountered in MMS and may even be present at the edge of other tumor types. Plaquelike syringoma has been reported as a coexistent entity with nodular basal cell carcinoma.¹² Boos et al¹⁶ similarly reported the presence of deceptive ductal proliferations along the immediate peripheral margin of MAC, which prompted multiple re-excisions. Pursuit of permanent section analysis in these cases revealed the appearance of small syringomas, and a diagnosis of benign subclinical syringomatous proliferations was made, averting further intervention.¹⁶

Our case sheds light on the threat of commission bias in dermatologic surgery, which is the tendency for action rather than inaction.¹⁷ In this context, it is important to avoid the perspective that harm to the patient can only be prevented by active intervention. Cognitive bias has been increasingly recognized as a source of medical error, and methods to mitigate bias in medical practice have been well described.¹⁷ Microcystic adnexal carcinoma and plaquelike syringoma can be hard to differentiate especially initially, as demonstrated in our case, which particularly illustrates the importance of slowing down a surgical case at the appropriate time, considering and revisiting alternative diagnoses, implementing checklists, and seeking histopathologic collaboration with colleagues when necessary. Our attempted implementation of these principles, especially early collaboration with colleagues, led to intraoperative recognition of plaquelike syringoma within the first stage of MMS.

We seek to raise the index of suspicion for plaquelike syringoma among dermatologists and dermatologic surgeons, especially when syringomatous structures are limited to the superficial dermis. We encourage familiarity with the plaquelike syringoma entity as well as careful consideration of further investigation via scouting biopsies or permanent section analysis when other characteristic features of MAC are unclear or lacking. Adequate sampling as well as collaboration with a dermatopathologist in cases of suspected syringoma can help to reduce the susceptibility to commission bias and prevent histopathologic pitfalls and unwarranted surgical morbidity.

To the Editor:

Plaquelike or plaque-type syringoma is a lesser-known variant of syringoma that can appear histologically indistinguishable from the superficial portion of microcystic adnexal carcinoma (MAC). The plaquelike variant of syringoma holds a benign clinical course, and no treatment is necessary. Microcystic adnexal carcinoma is distinguished from plaquelike syringoma by an aggressive growth pattern with a high risk for local invasion and recurrence if inadequately treated. Thus, treatment with Mohs micrographic surgery (MMS) has been recommended as the mainstay for MAC. If superficial biopsy specimens reveal suspicion for MAC and patients are referred for MMS, careful consideration should be made to differentiate MAC and plaquelike syringoma early to prevent unnecessary morbidity.

A 78-year-old woman was referred for MMS for a left forehead lesion that was diagnosed via shave biopsy as a desmoplastic and cystic adnexal neoplasm with suspicion for desmoplastic trichoepithelioma or MAC (Figure 1). Upon presentation for MMS, a well-healed, 1.0×0.9-cm scar at the biopsy site on the left forehead was observed (Figure 2A). One stage was obtained by standard MMS technique and sent for intraoperative processing (Figure 2B). Frozen section examination of the first stage demonstrated peripheral margin involvement with syringomatous change confined to the superficial and mid dermis (Figure 3). Before proceeding further, these findings were reviewed with an in-house dermatopathologist, and it was determined that no infiltrative tumor, perineural involvement, or other features to indicate malignancy were noted. A decision was made to refrain from obtaining any additional layers and to send excised Burow triangles for permanent section analysis. A primary linear closure was performed without complication, and the patient was discharged from the ambulatory surgery suite. Histopathologic examination of the Burow triangles later confirmed findings consistent with plaquelike syringoma with no evidence of malignancy (Figure 4).

Syringomas present as small flesh-colored papules in the periorbital areas. These benign neoplasms previously have been classified into 4 major clinical variants: localized, generalized, Down syndrome associated, and familial.¹ The lesser-known plaquelike variant of syringoma was first described by Kikuchi et al² in 1979. Aside from our report, a PubMed search of articles indexed for MEDLINE using the terms plaquelike or plaque-type syringoma yielded 16 cases in the literature.^2-14 Of these, 6 were referred to or encountered in the MMS setting.^8,9,11,12,14 Plaquelike syringoma can be solitary or multiple in presentation.⁶ It most commonly involves the head and neck but also can present on the trunk, arms, legs, and groin areas. The clinical size of plaquelike syringoma is variable, with the largest reported cases extending several centimeters in diameter.^2,6 Similar to reported associations with conventional syringoma, the plaquelike subtype of syringoma has been reported in association with Down syndrome.¹³

Histopathologically, plaquelike syringoma shares features with MAC as well as desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma. Plaquelike syringoma demonstrates broad proliferations of small tubules morphologically reminiscent of tadpoles confined within the dermis. Ducts typically are lined with 2 or 3 layers of small cuboidal cells. Microcystic adnexal carcinoma typically features asymmetric ductal structures lined with single cells extending from the dermis into the subcutis and even underlying muscle, cartilage, or bone.⁸ There are no reliable immunohistochemical stains to differentiate between these 2 entities; thus, the primary distinction lies in the depth of involvement. Desmoplastic trichoepithelioma is composed of narrow cords and nests of basaloid cells of follicular origin commonly admixed with small cornifying cysts appearing in the dermis.⁸ Colonizing Merkel cells positive for cytokeratin 20 often are present in desmoplastic trichoepithelioma and not in syringoma or MAC.¹⁵ Desmoplastic basal cell carcinoma demonstrates narrow strands of basaloid cells of follicular origin appearing in the dermis. Desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma are each fundamentally differentiated from plaquelike syringoma in that proliferations of cords and nests are not of eccrine or apocrine origin.

Several cases of plaquelike syringoma have been challenging to distinguish from MAC in performing MMS.^8,9,11 Underlying extension of this syringoma variant can be far-reaching, extending to several centimeters in size and involving multiple cosmetic subunits.^6,11,14 Inadvertent overtreatment with multiple MMS stages can be avoided with careful recognition of the differentiating histopathologic features. Syringomatous lesions commonly are encountered in MMS and may even be present at the edge of other tumor types. Plaquelike syringoma has been reported as a coexistent entity with nodular basal cell carcinoma.¹² Boos et al¹⁶ similarly reported the presence of deceptive ductal proliferations along the immediate peripheral margin of MAC, which prompted multiple re-excisions. Pursuit of permanent section analysis in these cases revealed the appearance of small syringomas, and a diagnosis of benign subclinical syringomatous proliferations was made, averting further intervention.¹⁶

Our case sheds light on the threat of commission bias in dermatologic surgery, which is the tendency for action rather than inaction.¹⁷ In this context, it is important to avoid the perspective that harm to the patient can only be prevented by active intervention. Cognitive bias has been increasingly recognized as a source of medical error, and methods to mitigate bias in medical practice have been well described.¹⁷ Microcystic adnexal carcinoma and plaquelike syringoma can be hard to differentiate especially initially, as demonstrated in our case, which particularly illustrates the importance of slowing down a surgical case at the appropriate time, considering and revisiting alternative diagnoses, implementing checklists, and seeking histopathologic collaboration with colleagues when necessary. Our attempted implementation of these principles, especially early collaboration with colleagues, led to intraoperative recognition of plaquelike syringoma within the first stage of MMS.

We seek to raise the index of suspicion for plaquelike syringoma among dermatologists and dermatologic surgeons, especially when syringomatous structures are limited to the superficial dermis. We encourage familiarity with the plaquelike syringoma entity as well as careful consideration of further investigation via scouting biopsies or permanent section analysis when other characteristic features of MAC are unclear or lacking. Adequate sampling as well as collaboration with a dermatopathologist in cases of suspected syringoma can help to reduce the susceptibility to commission bias and prevent histopathologic pitfalls and unwarranted surgical morbidity.

To the Editor:

Plaquelike or plaque-type syringoma is a lesser-known variant of syringoma that can appear histologically indistinguishable from the superficial portion of microcystic adnexal carcinoma (MAC). The plaquelike variant of syringoma holds a benign clinical course, and no treatment is necessary. Microcystic adnexal carcinoma is distinguished from plaquelike syringoma by an aggressive growth pattern with a high risk for local invasion and recurrence if inadequately treated. Thus, treatment with Mohs micrographic surgery (MMS) has been recommended as the mainstay for MAC. If superficial biopsy specimens reveal suspicion for MAC and patients are referred for MMS, careful consideration should be made to differentiate MAC and plaquelike syringoma early to prevent unnecessary morbidity.

A 78-year-old woman was referred for MMS for a left forehead lesion that was diagnosed via shave biopsy as a desmoplastic and cystic adnexal neoplasm with suspicion for desmoplastic trichoepithelioma or MAC (Figure 1). Upon presentation for MMS, a well-healed, 1.0×0.9-cm scar at the biopsy site on the left forehead was observed (Figure 2A). One stage was obtained by standard MMS technique and sent for intraoperative processing (Figure 2B). Frozen section examination of the first stage demonstrated peripheral margin involvement with syringomatous change confined to the superficial and mid dermis (Figure 3). Before proceeding further, these findings were reviewed with an in-house dermatopathologist, and it was determined that no infiltrative tumor, perineural involvement, or other features to indicate malignancy were noted. A decision was made to refrain from obtaining any additional layers and to send excised Burow triangles for permanent section analysis. A primary linear closure was performed without complication, and the patient was discharged from the ambulatory surgery suite. Histopathologic examination of the Burow triangles later confirmed findings consistent with plaquelike syringoma with no evidence of malignancy (Figure 4).

Syringomas present as small flesh-colored papules in the periorbital areas. These benign neoplasms previously have been classified into 4 major clinical variants: localized, generalized, Down syndrome associated, and familial.¹ The lesser-known plaquelike variant of syringoma was first described by Kikuchi et al² in 1979. Aside from our report, a PubMed search of articles indexed for MEDLINE using the terms plaquelike or plaque-type syringoma yielded 16 cases in the literature.^2-14 Of these, 6 were referred to or encountered in the MMS setting.^8,9,11,12,14 Plaquelike syringoma can be solitary or multiple in presentation.⁶ It most commonly involves the head and neck but also can present on the trunk, arms, legs, and groin areas. The clinical size of plaquelike syringoma is variable, with the largest reported cases extending several centimeters in diameter.^2,6 Similar to reported associations with conventional syringoma, the plaquelike subtype of syringoma has been reported in association with Down syndrome.¹³

Histopathologically, plaquelike syringoma shares features with MAC as well as desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma. Plaquelike syringoma demonstrates broad proliferations of small tubules morphologically reminiscent of tadpoles confined within the dermis. Ducts typically are lined with 2 or 3 layers of small cuboidal cells. Microcystic adnexal carcinoma typically features asymmetric ductal structures lined with single cells extending from the dermis into the subcutis and even underlying muscle, cartilage, or bone.⁸ There are no reliable immunohistochemical stains to differentiate between these 2 entities; thus, the primary distinction lies in the depth of involvement. Desmoplastic trichoepithelioma is composed of narrow cords and nests of basaloid cells of follicular origin commonly admixed with small cornifying cysts appearing in the dermis.⁸ Colonizing Merkel cells positive for cytokeratin 20 often are present in desmoplastic trichoepithelioma and not in syringoma or MAC.¹⁵ Desmoplastic basal cell carcinoma demonstrates narrow strands of basaloid cells of follicular origin appearing in the dermis. Desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma are each fundamentally differentiated from plaquelike syringoma in that proliferations of cords and nests are not of eccrine or apocrine origin.

Several cases of plaquelike syringoma have been challenging to distinguish from MAC in performing MMS.^8,9,11 Underlying extension of this syringoma variant can be far-reaching, extending to several centimeters in size and involving multiple cosmetic subunits.^6,11,14 Inadvertent overtreatment with multiple MMS stages can be avoided with careful recognition of the differentiating histopathologic features. Syringomatous lesions commonly are encountered in MMS and may even be present at the edge of other tumor types. Plaquelike syringoma has been reported as a coexistent entity with nodular basal cell carcinoma.¹² Boos et al¹⁶ similarly reported the presence of deceptive ductal proliferations along the immediate peripheral margin of MAC, which prompted multiple re-excisions. Pursuit of permanent section analysis in these cases revealed the appearance of small syringomas, and a diagnosis of benign subclinical syringomatous proliferations was made, averting further intervention.¹⁶

Our case sheds light on the threat of commission bias in dermatologic surgery, which is the tendency for action rather than inaction.¹⁷ In this context, it is important to avoid the perspective that harm to the patient can only be prevented by active intervention. Cognitive bias has been increasingly recognized as a source of medical error, and methods to mitigate bias in medical practice have been well described.¹⁷ Microcystic adnexal carcinoma and plaquelike syringoma can be hard to differentiate especially initially, as demonstrated in our case, which particularly illustrates the importance of slowing down a surgical case at the appropriate time, considering and revisiting alternative diagnoses, implementing checklists, and seeking histopathologic collaboration with colleagues when necessary. Our attempted implementation of these principles, especially early collaboration with colleagues, led to intraoperative recognition of plaquelike syringoma within the first stage of MMS.

We seek to raise the index of suspicion for plaquelike syringoma among dermatologists and dermatologic surgeons, especially when syringomatous structures are limited to the superficial dermis. We encourage familiarity with the plaquelike syringoma entity as well as careful consideration of further investigation via scouting biopsies or permanent section analysis when other characteristic features of MAC are unclear or lacking. Adequate sampling as well as collaboration with a dermatopathologist in cases of suspected syringoma can help to reduce the susceptibility to commission bias and prevent histopathologic pitfalls and unwarranted surgical morbidity.

To the Editor:

A 16-year-old adolescent boy presented to our pediatric dermatology clinic for evaluation of long-standing mild atopic dermatitis (AD) that had become severe over the last year after omalizumab was initiated for severe asthma. The patient had a history of multiple hospitalizations for severe asthma. Despite excellent control of asthma with omalizumab given every 2 weeks, he developed widespread eczematous plaques on the neck, trunk, and extremities over the course of a year. The AD often was complicated by superimposed folliculitis due to scratching from severe pruritus. Treatment with topical corticosteroids including triamcinolone ointment 0.1% to AD on the body, plus clobetasol ointment 0.05% for prurigolike lesions on the legs resulted in modest improvement; however, the AD consistently recurred within a few days after the biweekly omalizumab injection (Figure 1). When the omalizumab injections were delayed, the flares temporarily improved, and when injections were decreased to once monthly, the exacerbations subsided partially but not fully.

Because omalizumab resulted in dramatic improvement in the patient’s asthma, there was hesitation to discontinue it initially; however, the patient and his parents in conjunction with the dermatology and pulmonary teams decided to transition to dupilumab. The patient reported vast improvement of AD 1 month after initiation of dupilumab (Figure 2), which remained well controlled more than 1 year later. Mid-potency topical corticosteroids for the treatment of occasional mild eczematous flares on the extremities were used. The patient’s asthma has remained well controlled on dupilumab without any exacerbations.

Omalizumab is a recombinant DNA-derived humanized monoclonal antibody that binds both circulating and membrane-bound IgE. It has been proposed as a possible treatment for severe and/or recalcitrant AD, with mixed treatment results.¹ A case series and review of 174 patients demonstrated a moderate to complete AD response to treatment with omalizumab in 74.1% of patients.² The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) showed a statistically significant reduction in the Scoring Atopic Dermatitis (SCORAD) index (P=.01), along with improved quality of life in children treated with omalizumab vs those treated with placebo.³ However, a prior randomized, placebo-controlled, double-blind study did not show a significant difference in clinical disease parameters in patients treated with omalizumab.⁴

The humanized monoclonal antibody dupilumab, an anti–IL-4/IL-13 agent, has demonstrated more consistent efficacy for the treatment of AD in children and adults.¹ Dupilumab is effective for both intrinsic and extrinsic AD¹ because its clinical efficacy is unrelated to circulating levels of IgE in the bloodstream. Although IgE may have a role in childhood AD, our case demonstrated a different pathophysiologic mechanism independent of IgE. Our patient’s AD flares occurred within a few days of omalizumab injection, which may have resulted in a paradoxical increase in basophil sensitivity to other cytokines such as IL-33⁵ and led to an increase in IL-4/IL-13 production within the skin. In our patient, this increase was successfully blocked by dupilumab. Furthermore, omalizumab has been shown to modulate helper T cell (T_H2) cytokine response such as thymic stromal lymphopoietin.⁶ A cytokine imbalance could have exacerbated AD in our case.

Although additional work to clarify the pathogenesis of AD is needed, it is important to recognize the potential for the occurrence of paradoxical AD flares in patients treated with omalizumab, which is analogous to the well-documented entity of tumor necrosis factor α inhibitor–induced psoriasis. It is equally important to recognize the potential benefit for patients treated with dupilumab.

To the Editor:

A 16-year-old adolescent boy presented to our pediatric dermatology clinic for evaluation of long-standing mild atopic dermatitis (AD) that had become severe over the last year after omalizumab was initiated for severe asthma. The patient had a history of multiple hospitalizations for severe asthma. Despite excellent control of asthma with omalizumab given every 2 weeks, he developed widespread eczematous plaques on the neck, trunk, and extremities over the course of a year. The AD often was complicated by superimposed folliculitis due to scratching from severe pruritus. Treatment with topical corticosteroids including triamcinolone ointment 0.1% to AD on the body, plus clobetasol ointment 0.05% for prurigolike lesions on the legs resulted in modest improvement; however, the AD consistently recurred within a few days after the biweekly omalizumab injection (Figure 1). When the omalizumab injections were delayed, the flares temporarily improved, and when injections were decreased to once monthly, the exacerbations subsided partially but not fully.

Because omalizumab resulted in dramatic improvement in the patient’s asthma, there was hesitation to discontinue it initially; however, the patient and his parents in conjunction with the dermatology and pulmonary teams decided to transition to dupilumab. The patient reported vast improvement of AD 1 month after initiation of dupilumab (Figure 2), which remained well controlled more than 1 year later. Mid-potency topical corticosteroids for the treatment of occasional mild eczematous flares on the extremities were used. The patient’s asthma has remained well controlled on dupilumab without any exacerbations.

Omalizumab is a recombinant DNA-derived humanized monoclonal antibody that binds both circulating and membrane-bound IgE. It has been proposed as a possible treatment for severe and/or recalcitrant AD, with mixed treatment results.¹ A case series and review of 174 patients demonstrated a moderate to complete AD response to treatment with omalizumab in 74.1% of patients.² The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) showed a statistically significant reduction in the Scoring Atopic Dermatitis (SCORAD) index (P=.01), along with improved quality of life in children treated with omalizumab vs those treated with placebo.³ However, a prior randomized, placebo-controlled, double-blind study did not show a significant difference in clinical disease parameters in patients treated with omalizumab.⁴

The humanized monoclonal antibody dupilumab, an anti–IL-4/IL-13 agent, has demonstrated more consistent efficacy for the treatment of AD in children and adults.¹ Dupilumab is effective for both intrinsic and extrinsic AD¹ because its clinical efficacy is unrelated to circulating levels of IgE in the bloodstream. Although IgE may have a role in childhood AD, our case demonstrated a different pathophysiologic mechanism independent of IgE. Our patient’s AD flares occurred within a few days of omalizumab injection, which may have resulted in a paradoxical increase in basophil sensitivity to other cytokines such as IL-33⁵ and led to an increase in IL-4/IL-13 production within the skin. In our patient, this increase was successfully blocked by dupilumab. Furthermore, omalizumab has been shown to modulate helper T cell (T_H2) cytokine response such as thymic stromal lymphopoietin.⁶ A cytokine imbalance could have exacerbated AD in our case.

Although additional work to clarify the pathogenesis of AD is needed, it is important to recognize the potential for the occurrence of paradoxical AD flares in patients treated with omalizumab, which is analogous to the well-documented entity of tumor necrosis factor α inhibitor–induced psoriasis. It is equally important to recognize the potential benefit for patients treated with dupilumab.

To the Editor:

A 16-year-old adolescent boy presented to our pediatric dermatology clinic for evaluation of long-standing mild atopic dermatitis (AD) that had become severe over the last year after omalizumab was initiated for severe asthma. The patient had a history of multiple hospitalizations for severe asthma. Despite excellent control of asthma with omalizumab given every 2 weeks, he developed widespread eczematous plaques on the neck, trunk, and extremities over the course of a year. The AD often was complicated by superimposed folliculitis due to scratching from severe pruritus. Treatment with topical corticosteroids including triamcinolone ointment 0.1% to AD on the body, plus clobetasol ointment 0.05% for prurigolike lesions on the legs resulted in modest improvement; however, the AD consistently recurred within a few days after the biweekly omalizumab injection (Figure 1). When the omalizumab injections were delayed, the flares temporarily improved, and when injections were decreased to once monthly, the exacerbations subsided partially but not fully.

Because omalizumab resulted in dramatic improvement in the patient’s asthma, there was hesitation to discontinue it initially; however, the patient and his parents in conjunction with the dermatology and pulmonary teams decided to transition to dupilumab. The patient reported vast improvement of AD 1 month after initiation of dupilumab (Figure 2), which remained well controlled more than 1 year later. Mid-potency topical corticosteroids for the treatment of occasional mild eczematous flares on the extremities were used. The patient’s asthma has remained well controlled on dupilumab without any exacerbations.

Omalizumab is a recombinant DNA-derived humanized monoclonal antibody that binds both circulating and membrane-bound IgE. It has been proposed as a possible treatment for severe and/or recalcitrant AD, with mixed treatment results.¹ A case series and review of 174 patients demonstrated a moderate to complete AD response to treatment with omalizumab in 74.1% of patients.² The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) showed a statistically significant reduction in the Scoring Atopic Dermatitis (SCORAD) index (P=.01), along with improved quality of life in children treated with omalizumab vs those treated with placebo.³ However, a prior randomized, placebo-controlled, double-blind study did not show a significant difference in clinical disease parameters in patients treated with omalizumab.⁴

The humanized monoclonal antibody dupilumab, an anti–IL-4/IL-13 agent, has demonstrated more consistent efficacy for the treatment of AD in children and adults.¹ Dupilumab is effective for both intrinsic and extrinsic AD¹ because its clinical efficacy is unrelated to circulating levels of IgE in the bloodstream. Although IgE may have a role in childhood AD, our case demonstrated a different pathophysiologic mechanism independent of IgE. Our patient’s AD flares occurred within a few days of omalizumab injection, which may have resulted in a paradoxical increase in basophil sensitivity to other cytokines such as IL-33⁵ and led to an increase in IL-4/IL-13 production within the skin. In our patient, this increase was successfully blocked by dupilumab. Furthermore, omalizumab has been shown to modulate helper T cell (T_H2) cytokine response such as thymic stromal lymphopoietin.⁶ A cytokine imbalance could have exacerbated AD in our case.

Although additional work to clarify the pathogenesis of AD is needed, it is important to recognize the potential for the occurrence of paradoxical AD flares in patients treated with omalizumab, which is analogous to the well-documented entity of tumor necrosis factor α inhibitor–induced psoriasis. It is equally important to recognize the potential benefit for patients treated with dupilumab.

To the Editor:

Metastatic spread of salivary duct carcinoma (SDC) to the skin is rare. Diagnosing SDC can be challenging because the cutaneous manifestations of this disease are variable and include nodules, papules, and erysipelaslike inflammation (also known as shield sign) with purpuric papules and pseudovesicles. We describe a case of cutaneous metastatic SDC that originated from the parotid gland and presented with 2 distinct cutaneous findings: sharply demarcated erythematous plaques and focally hemorrhagic angiomatous papules.

A 60-year-old man presented with a persistent polymorphous pruritic eruption of several months’ duration involving the entire face, ears, neck, and upper chest. He had a history of unspecified adenocarcinoma of the parotid gland diagnosed 2 years prior and underwent multiple treatment cycles with several chemotherapeutic agents over the course of 18 months. Physical examination showed erythematous papules and nodules on the face and neck with slight overlying scale. Sharply demarcated, erythematous plaques studded with focally hemorrhagic, angiomatous papules were noted on the neck and chest (Figure 1). Two 4-mm punch biopsies were sampled from representative nodular areas. Histopathology showed multiple round solid-tumor nodules with central necrosis in the superficial and deep dermis that were not associated with the overlying epidermis (Figures 2A and 2B). The tumor cells appeared polygonal and contained ample eosinophilic cytoplasm. Tumor nuclei showed marked pleomorphism, and numerous atypical mitotic figures were readily identifiable (Figure 2C). There was diffuse cytoplasmic staining with cytokeratin 7 and nuclear staining with androgen receptor (Figure 2D). These findings were consistent with a diagnosis of SDC metastatic to the skin.

The patient underwent 8 cycles of docetaxel chemotherapy. With disease progression, the chemotherapy regimen was changed to gemcitabine and methotrexate. The patient continued to experience disease progression and died 9 months after diagnosis of skin metastases.

Salivary duct carcinoma is rare and is estimated to represent 1% to 3% of all salivary malignancies.¹ It is a highly aggressive form of salivary gland carcinoma and is associated with a poor clinical outcome. The 3-year overall survival rate for stage I disease is 42% and only 23% for stage IV disease.² Salivary duct carcinoma has a high rate of distant metastasis,³ but cases of cutaneous metastases are rare.^3-8 Previously reported cases of SDC that metastasized to the skin originated from the parotid gland (n=6) and submandibular gland (n=1).³

The diagnosis of cutaneous metastases is challenging due to the variability of the skin manifestations. Three cases described small firm nodules in patients,^3-5 while others presented with purpuric papules and pseudovesicles.^6-8 Our patient presented with sharply demarcated, erythematous plaques studded with focally hemorrhagic, angiomatous papules, which further emphasizes the capricious nature of skin findings.

The morphology of SDC is strikingly similar to ductal adenocarcinoma of the breast, which can lead to diagnostic confusion. Both carcinomas may show oncocytic cells, ductal formations, and cribriform structures with central comedo necrosis. Moreover, immunohistochemical features overlap, including positive staining for cytokeratin 7 and gross cystic disease fluid protein 15. Positive immunohistochemistry with androgen receptor is consistent with SDC but also can be expressed in some cases of breast carcinoma.^9,10 Therefore, the diagnosis of cutaneous involvement from metastatic SDC requires not just an evaluation of the pathologic features but careful attention to the clinical history and a thorough staging evaluation.

To the Editor:

Metastatic spread of salivary duct carcinoma (SDC) to the skin is rare. Diagnosing SDC can be challenging because the cutaneous manifestations of this disease are variable and include nodules, papules, and erysipelaslike inflammation (also known as shield sign) with purpuric papules and pseudovesicles. We describe a case of cutaneous metastatic SDC that originated from the parotid gland and presented with 2 distinct cutaneous findings: sharply demarcated erythematous plaques and focally hemorrhagic angiomatous papules.

A 60-year-old man presented with a persistent polymorphous pruritic eruption of several months’ duration involving the entire face, ears, neck, and upper chest. He had a history of unspecified adenocarcinoma of the parotid gland diagnosed 2 years prior and underwent multiple treatment cycles with several chemotherapeutic agents over the course of 18 months. Physical examination showed erythematous papules and nodules on the face and neck with slight overlying scale. Sharply demarcated, erythematous plaques studded with focally hemorrhagic, angiomatous papules were noted on the neck and chest (Figure 1). Two 4-mm punch biopsies were sampled from representative nodular areas. Histopathology showed multiple round solid-tumor nodules with central necrosis in the superficial and deep dermis that were not associated with the overlying epidermis (Figures 2A and 2B). The tumor cells appeared polygonal and contained ample eosinophilic cytoplasm. Tumor nuclei showed marked pleomorphism, and numerous atypical mitotic figures were readily identifiable (Figure 2C). There was diffuse cytoplasmic staining with cytokeratin 7 and nuclear staining with androgen receptor (Figure 2D). These findings were consistent with a diagnosis of SDC metastatic to the skin.

The patient underwent 8 cycles of docetaxel chemotherapy. With disease progression, the chemotherapy regimen was changed to gemcitabine and methotrexate. The patient continued to experience disease progression and died 9 months after diagnosis of skin metastases.

Salivary duct carcinoma is rare and is estimated to represent 1% to 3% of all salivary malignancies.¹ It is a highly aggressive form of salivary gland carcinoma and is associated with a poor clinical outcome. The 3-year overall survival rate for stage I disease is 42% and only 23% for stage IV disease.² Salivary duct carcinoma has a high rate of distant metastasis,³ but cases of cutaneous metastases are rare.^3-8 Previously reported cases of SDC that metastasized to the skin originated from the parotid gland (n=6) and submandibular gland (n=1).³

The diagnosis of cutaneous metastases is challenging due to the variability of the skin manifestations. Three cases described small firm nodules in patients,^3-5 while others presented with purpuric papules and pseudovesicles.^6-8 Our patient presented with sharply demarcated, erythematous plaques studded with focally hemorrhagic, angiomatous papules, which further emphasizes the capricious nature of skin findings.

The morphology of SDC is strikingly similar to ductal adenocarcinoma of the breast, which can lead to diagnostic confusion. Both carcinomas may show oncocytic cells, ductal formations, and cribriform structures with central comedo necrosis. Moreover, immunohistochemical features overlap, including positive staining for cytokeratin 7 and gross cystic disease fluid protein 15. Positive immunohistochemistry with androgen receptor is consistent with SDC but also can be expressed in some cases of breast carcinoma.^9,10 Therefore, the diagnosis of cutaneous involvement from metastatic SDC requires not just an evaluation of the pathologic features but careful attention to the clinical history and a thorough staging evaluation.

To the Editor:

Metastatic spread of salivary duct carcinoma (SDC) to the skin is rare. Diagnosing SDC can be challenging because the cutaneous manifestations of this disease are variable and include nodules, papules, and erysipelaslike inflammation (also known as shield sign) with purpuric papules and pseudovesicles. We describe a case of cutaneous metastatic SDC that originated from the parotid gland and presented with 2 distinct cutaneous findings: sharply demarcated erythematous plaques and focally hemorrhagic angiomatous papules.

A 60-year-old man presented with a persistent polymorphous pruritic eruption of several months’ duration involving the entire face, ears, neck, and upper chest. He had a history of unspecified adenocarcinoma of the parotid gland diagnosed 2 years prior and underwent multiple treatment cycles with several chemotherapeutic agents over the course of 18 months. Physical examination showed erythematous papules and nodules on the face and neck with slight overlying scale. Sharply demarcated, erythematous plaques studded with focally hemorrhagic, angiomatous papules were noted on the neck and chest (Figure 1). Two 4-mm punch biopsies were sampled from representative nodular areas. Histopathology showed multiple round solid-tumor nodules with central necrosis in the superficial and deep dermis that were not associated with the overlying epidermis (Figures 2A and 2B). The tumor cells appeared polygonal and contained ample eosinophilic cytoplasm. Tumor nuclei showed marked pleomorphism, and numerous atypical mitotic figures were readily identifiable (Figure 2C). There was diffuse cytoplasmic staining with cytokeratin 7 and nuclear staining with androgen receptor (Figure 2D). These findings were consistent with a diagnosis of SDC metastatic to the skin.

The patient underwent 8 cycles of docetaxel chemotherapy. With disease progression, the chemotherapy regimen was changed to gemcitabine and methotrexate. The patient continued to experience disease progression and died 9 months after diagnosis of skin metastases.

Salivary duct carcinoma is rare and is estimated to represent 1% to 3% of all salivary malignancies.¹ It is a highly aggressive form of salivary gland carcinoma and is associated with a poor clinical outcome. The 3-year overall survival rate for stage I disease is 42% and only 23% for stage IV disease.² Salivary duct carcinoma has a high rate of distant metastasis,³ but cases of cutaneous metastases are rare.^3-8 Previously reported cases of SDC that metastasized to the skin originated from the parotid gland (n=6) and submandibular gland (n=1).³

The diagnosis of cutaneous metastases is challenging due to the variability of the skin manifestations. Three cases described small firm nodules in patients,^3-5 while others presented with purpuric papules and pseudovesicles.^6-8 Our patient presented with sharply demarcated, erythematous plaques studded with focally hemorrhagic, angiomatous papules, which further emphasizes the capricious nature of skin findings.

The morphology of SDC is strikingly similar to ductal adenocarcinoma of the breast, which can lead to diagnostic confusion. Both carcinomas may show oncocytic cells, ductal formations, and cribriform structures with central comedo necrosis. Moreover, immunohistochemical features overlap, including positive staining for cytokeratin 7 and gross cystic disease fluid protein 15. Positive immunohistochemistry with androgen receptor is consistent with SDC but also can be expressed in some cases of breast carcinoma.^9,10 Therefore, the diagnosis of cutaneous involvement from metastatic SDC requires not just an evaluation of the pathologic features but careful attention to the clinical history and a thorough staging evaluation.

To the Editor:

A woman in her 40s presented with acute onset of rapidly spreading lesions on the face, trunk, and extremities. She reported high fever and endorsed malaise. She had a history of end-stage renal disease and was on renal dialysis. She recently underwent revision of an arteriovenous fistula.

Physical examination revealed diffuse, erythematous, firm papules and plaques with central hemorrhage and umbilication on the dorsal aspect of the nose, forehead, temples, and cheeks. There also were purpuric papules and plaques with a peripheral rim of vesiculation (Figure 1) on the medial and posterior thighs and buttocks. Histopathology of a biopsy specimen revealed an interstitial neutrophilic infiltrate in the superficial dermis and mid dermis with scattered, haloed, acellular structures simulating cryptococcal organisms (Figure 2). Periodic acid–Schiff (PAS), Grocott methenamine-silver, and mucicarmine staining was negative. Repeat biopsy showed similar findings. A (1-3)-β-d glucan assay for invasive fungal infection and tests for serum cryptococcal antigen, serum Coccidioides antibody, serum Blastomyces antigen, and urine and serum Histoplasma antigen were negative. A fungal complement fixation battery was negative. Blood and tissue cultures for bacteria, anaerobes, fungi, and acid-fast bacilli remained sterile. Swabs were negative for varicella-zoster virus and herpes simplex virus. Urine and blood iodine levels were 344,998 μg/L (reference range, 34–523 μg/L) and 47,459 μg/L (reference range, 52–109 μg/L), respectively. The elevated iodine levels were presumed to be secondary to iodinated contrast media that the patient received for revision of the arteriovenous fistula.

The findings compatible with a diagnosis of iododerma included umbilicated hemorrhagic papules and plaques, cryptococcal-like structures with negative staining on histopathology, and elevated iodine levels with a negative infectious workup. The patient was treated with topical corticosteroids. At 1-month follow-up, the lesions had resolved.

Iododerma is a halogenoderma, a skin eruption that occurs after ingestion of or exposure to a halogen-containing substance (eg, iodine, bromine, fluorine) or medication (eg, lithium).¹ Common sources of iodine include iodinated contrast media, potassium iodide ingestion, topical application of povidone–iodine, radioactive iodine administration, and the antiarrhythmic amiodarone. Excess exposure to iodine-containing compounds typically occurs in the setting of kidney disease or failure as well as due to reduced iodine clearance.¹ Although the pathogenesis of iododerma is unknown, the most common hypothesis is that lesions are delayed hypersensitivity reactions secondary to formation of a protein-halogen complex.²

The presentation of iododerma is polymorphous and includes acneform, vegetative, or pustular eruptions; umbilicated papules and plaques can be present.^2,3 Lesions can be either asymptomatic or painful and pruritic. Timing between iodine exposure and onset of lesions varies from hours to days to years.^2,4

Systemic symptoms of iododerma can occur, including salivary gland swelling, hypotension and bradycardia, kidney injury, or thyroid and liver abnormalities. Histopathologic analysis demonstrates a dense neutrophilic dermatitis with negative staining for infectious causes.^4,5 Cryptococcal-like structures have been described in iododerma³; neutrophilic dermatoses of various causes that mimic cryptococcal infection have been reported.⁶ Ultimately, iododerma remains a diagnosis of exclusion.

Withdrawal of an offending compound is remedial. Dialysis is beneficial in end-stage renal disease. Topical, intralesional, and systemic corticosteroids, as well as antibiotics, provide variable benefit.^4,7 Lesions can take 4 to 6 weeks to clear after withdrawal of the offending agent. It is unclear whether recurrences happen; iodine-containing compounds need to be avoided after a patient has been affected.

Iododerma has a broad differential diagnosis due to the polymorphous presentation of the disorder, including acute febrile neutrophilic dermatosis (also known as Sweet syndrome), cutaneous cryptococcosis, and cutaneous histoplasmosis. Sweet syndrome presents as abrupt onset of edematous erythematous plaques with fever and leukocytosis. It is associated with infection, inflammatory disorders, medication, and malignancy.⁸ Histopathologic analysis reveals papillary dermal edema and a neutrophilic dermatosis. Cytoplasmic vacuolization resembling C neoformans has been reported.⁹ The diagnosis is less favored in the presence of renal disease, temporal association of the eruption with iodine exposure, and elevated blood and urine iodine levels, as in our patient.

Cutaneous cryptococcosis, an infection caused by C neoformans, typically occurs secondary to dissemination from the lungs; rarely, the disease is primary. Acneform plaques, vegetative plaques, and umbilicated lesions are seen.¹⁰ Histopathologic analysis shows characteristic yeast forms of cryptococcosis surrounded by gelatinous edema, which create a haloed effect, typically throughout the dermis. Capsules are positive for PAS or mucicarmine staining. Although C neoformans can closely mimic iododerma both clinically and histopathologically, negative infectious staining, localization of haloed structures to the upper dermis, a negative test for cryptococcal antigen, and elevated blood and urine iodine levels in this case all favored iododerma.

Cutaneous histoplasmosis is an infection caused by Histoplasma capsulatum, most commonly as secondary dissemination from pulmonary infection but rarely from direct inoculation of the skin.¹¹ Presentation includes erythematous to hemorrhagic, umbilicated papules and plaques. Histopathologic findings are round to oval, narrow-based, budding yeasts that stain positive for PAS or mucicarmine. Although histoplasmosis can clinically mimic iododerma, the disease is distinguished histologically by the presence of fungal microorganisms that lack the gelatinous edema and haloed effect of iododerma.

We presented a unique case of iododerma simulating cryptococcal infection both clinically and histopathologically. Prompt recognition of histologic mimickers of true infectious microorganisms is essential to prevent unnecessary delay of withdrawal of the offending substance and to initiate appropriate therapy.

To the Editor:

A woman in her 40s presented with acute onset of rapidly spreading lesions on the face, trunk, and extremities. She reported high fever and endorsed malaise. She had a history of end-stage renal disease and was on renal dialysis. She recently underwent revision of an arteriovenous fistula.

Physical examination revealed diffuse, erythematous, firm papules and plaques with central hemorrhage and umbilication on the dorsal aspect of the nose, forehead, temples, and cheeks. There also were purpuric papules and plaques with a peripheral rim of vesiculation (Figure 1) on the medial and posterior thighs and buttocks. Histopathology of a biopsy specimen revealed an interstitial neutrophilic infiltrate in the superficial dermis and mid dermis with scattered, haloed, acellular structures simulating cryptococcal organisms (Figure 2). Periodic acid–Schiff (PAS), Grocott methenamine-silver, and mucicarmine staining was negative. Repeat biopsy showed similar findings. A (1-3)-β-d glucan assay for invasive fungal infection and tests for serum cryptococcal antigen, serum Coccidioides antibody, serum Blastomyces antigen, and urine and serum Histoplasma antigen were negative. A fungal complement fixation battery was negative. Blood and tissue cultures for bacteria, anaerobes, fungi, and acid-fast bacilli remained sterile. Swabs were negative for varicella-zoster virus and herpes simplex virus. Urine and blood iodine levels were 344,998 μg/L (reference range, 34–523 μg/L) and 47,459 μg/L (reference range, 52–109 μg/L), respectively. The elevated iodine levels were presumed to be secondary to iodinated contrast media that the patient received for revision of the arteriovenous fistula.

The findings compatible with a diagnosis of iododerma included umbilicated hemorrhagic papules and plaques, cryptococcal-like structures with negative staining on histopathology, and elevated iodine levels with a negative infectious workup. The patient was treated with topical corticosteroids. At 1-month follow-up, the lesions had resolved.

Iododerma is a halogenoderma, a skin eruption that occurs after ingestion of or exposure to a halogen-containing substance (eg, iodine, bromine, fluorine) or medication (eg, lithium).¹ Common sources of iodine include iodinated contrast media, potassium iodide ingestion, topical application of povidone–iodine, radioactive iodine administration, and the antiarrhythmic amiodarone. Excess exposure to iodine-containing compounds typically occurs in the setting of kidney disease or failure as well as due to reduced iodine clearance.¹ Although the pathogenesis of iododerma is unknown, the most common hypothesis is that lesions are delayed hypersensitivity reactions secondary to formation of a protein-halogen complex.²

The presentation of iododerma is polymorphous and includes acneform, vegetative, or pustular eruptions; umbilicated papules and plaques can be present.^2,3 Lesions can be either asymptomatic or painful and pruritic. Timing between iodine exposure and onset of lesions varies from hours to days to years.^2,4

Systemic symptoms of iododerma can occur, including salivary gland swelling, hypotension and bradycardia, kidney injury, or thyroid and liver abnormalities. Histopathologic analysis demonstrates a dense neutrophilic dermatitis with negative staining for infectious causes.^4,5 Cryptococcal-like structures have been described in iododerma³; neutrophilic dermatoses of various causes that mimic cryptococcal infection have been reported.⁶ Ultimately, iododerma remains a diagnosis of exclusion.

Withdrawal of an offending compound is remedial. Dialysis is beneficial in end-stage renal disease. Topical, intralesional, and systemic corticosteroids, as well as antibiotics, provide variable benefit.^4,7 Lesions can take 4 to 6 weeks to clear after withdrawal of the offending agent. It is unclear whether recurrences happen; iodine-containing compounds need to be avoided after a patient has been affected.

Iododerma has a broad differential diagnosis due to the polymorphous presentation of the disorder, including acute febrile neutrophilic dermatosis (also known as Sweet syndrome), cutaneous cryptococcosis, and cutaneous histoplasmosis. Sweet syndrome presents as abrupt onset of edematous erythematous plaques with fever and leukocytosis. It is associated with infection, inflammatory disorders, medication, and malignancy.⁸ Histopathologic analysis reveals papillary dermal edema and a neutrophilic dermatosis. Cytoplasmic vacuolization resembling C neoformans has been reported.⁹ The diagnosis is less favored in the presence of renal disease, temporal association of the eruption with iodine exposure, and elevated blood and urine iodine levels, as in our patient.

Cutaneous cryptococcosis, an infection caused by C neoformans, typically occurs secondary to dissemination from the lungs; rarely, the disease is primary. Acneform plaques, vegetative plaques, and umbilicated lesions are seen.¹⁰ Histopathologic analysis shows characteristic yeast forms of cryptococcosis surrounded by gelatinous edema, which create a haloed effect, typically throughout the dermis. Capsules are positive for PAS or mucicarmine staining. Although C neoformans can closely mimic iododerma both clinically and histopathologically, negative infectious staining, localization of haloed structures to the upper dermis, a negative test for cryptococcal antigen, and elevated blood and urine iodine levels in this case all favored iododerma.

Cutaneous histoplasmosis is an infection caused by Histoplasma capsulatum, most commonly as secondary dissemination from pulmonary infection but rarely from direct inoculation of the skin.¹¹ Presentation includes erythematous to hemorrhagic, umbilicated papules and plaques. Histopathologic findings are round to oval, narrow-based, budding yeasts that stain positive for PAS or mucicarmine. Although histoplasmosis can clinically mimic iododerma, the disease is distinguished histologically by the presence of fungal microorganisms that lack the gelatinous edema and haloed effect of iododerma.

We presented a unique case of iododerma simulating cryptococcal infection both clinically and histopathologically. Prompt recognition of histologic mimickers of true infectious microorganisms is essential to prevent unnecessary delay of withdrawal of the offending substance and to initiate appropriate therapy.

To the Editor:

A woman in her 40s presented with acute onset of rapidly spreading lesions on the face, trunk, and extremities. She reported high fever and endorsed malaise. She had a history of end-stage renal disease and was on renal dialysis. She recently underwent revision of an arteriovenous fistula.

Physical examination revealed diffuse, erythematous, firm papules and plaques with central hemorrhage and umbilication on the dorsal aspect of the nose, forehead, temples, and cheeks. There also were purpuric papules and plaques with a peripheral rim of vesiculation (Figure 1) on the medial and posterior thighs and buttocks. Histopathology of a biopsy specimen revealed an interstitial neutrophilic infiltrate in the superficial dermis and mid dermis with scattered, haloed, acellular structures simulating cryptococcal organisms (Figure 2). Periodic acid–Schiff (PAS), Grocott methenamine-silver, and mucicarmine staining was negative. Repeat biopsy showed similar findings. A (1-3)-β-d glucan assay for invasive fungal infection and tests for serum cryptococcal antigen, serum Coccidioides antibody, serum Blastomyces antigen, and urine and serum Histoplasma antigen were negative. A fungal complement fixation battery was negative. Blood and tissue cultures for bacteria, anaerobes, fungi, and acid-fast bacilli remained sterile. Swabs were negative for varicella-zoster virus and herpes simplex virus. Urine and blood iodine levels were 344,998 μg/L (reference range, 34–523 μg/L) and 47,459 μg/L (reference range, 52–109 μg/L), respectively. The elevated iodine levels were presumed to be secondary to iodinated contrast media that the patient received for revision of the arteriovenous fistula.

The findings compatible with a diagnosis of iododerma included umbilicated hemorrhagic papules and plaques, cryptococcal-like structures with negative staining on histopathology, and elevated iodine levels with a negative infectious workup. The patient was treated with topical corticosteroids. At 1-month follow-up, the lesions had resolved.

Iododerma is a halogenoderma, a skin eruption that occurs after ingestion of or exposure to a halogen-containing substance (eg, iodine, bromine, fluorine) or medication (eg, lithium).¹ Common sources of iodine include iodinated contrast media, potassium iodide ingestion, topical application of povidone–iodine, radioactive iodine administration, and the antiarrhythmic amiodarone. Excess exposure to iodine-containing compounds typically occurs in the setting of kidney disease or failure as well as due to reduced iodine clearance.¹ Although the pathogenesis of iododerma is unknown, the most common hypothesis is that lesions are delayed hypersensitivity reactions secondary to formation of a protein-halogen complex.²

The presentation of iododerma is polymorphous and includes acneform, vegetative, or pustular eruptions; umbilicated papules and plaques can be present.^2,3 Lesions can be either asymptomatic or painful and pruritic. Timing between iodine exposure and onset of lesions varies from hours to days to years.^2,4

Systemic symptoms of iododerma can occur, including salivary gland swelling, hypotension and bradycardia, kidney injury, or thyroid and liver abnormalities. Histopathologic analysis demonstrates a dense neutrophilic dermatitis with negative staining for infectious causes.^4,5 Cryptococcal-like structures have been described in iododerma³; neutrophilic dermatoses of various causes that mimic cryptococcal infection have been reported.⁶ Ultimately, iododerma remains a diagnosis of exclusion.

Withdrawal of an offending compound is remedial. Dialysis is beneficial in end-stage renal disease. Topical, intralesional, and systemic corticosteroids, as well as antibiotics, provide variable benefit.^4,7 Lesions can take 4 to 6 weeks to clear after withdrawal of the offending agent. It is unclear whether recurrences happen; iodine-containing compounds need to be avoided after a patient has been affected.

Iododerma has a broad differential diagnosis due to the polymorphous presentation of the disorder, including acute febrile neutrophilic dermatosis (also known as Sweet syndrome), cutaneous cryptococcosis, and cutaneous histoplasmosis. Sweet syndrome presents as abrupt onset of edematous erythematous plaques with fever and leukocytosis. It is associated with infection, inflammatory disorders, medication, and malignancy.⁸ Histopathologic analysis reveals papillary dermal edema and a neutrophilic dermatosis. Cytoplasmic vacuolization resembling C neoformans has been reported.⁹ The diagnosis is less favored in the presence of renal disease, temporal association of the eruption with iodine exposure, and elevated blood and urine iodine levels, as in our patient.

Cutaneous cryptococcosis, an infection caused by C neoformans, typically occurs secondary to dissemination from the lungs; rarely, the disease is primary. Acneform plaques, vegetative plaques, and umbilicated lesions are seen.¹⁰ Histopathologic analysis shows characteristic yeast forms of cryptococcosis surrounded by gelatinous edema, which create a haloed effect, typically throughout the dermis. Capsules are positive for PAS or mucicarmine staining. Although C neoformans can closely mimic iododerma both clinically and histopathologically, negative infectious staining, localization of haloed structures to the upper dermis, a negative test for cryptococcal antigen, and elevated blood and urine iodine levels in this case all favored iododerma.

Cutaneous histoplasmosis is an infection caused by Histoplasma capsulatum, most commonly as secondary dissemination from pulmonary infection but rarely from direct inoculation of the skin.¹¹ Presentation includes erythematous to hemorrhagic, umbilicated papules and plaques. Histopathologic findings are round to oval, narrow-based, budding yeasts that stain positive for PAS or mucicarmine. Although histoplasmosis can clinically mimic iododerma, the disease is distinguished histologically by the presence of fungal microorganisms that lack the gelatinous edema and haloed effect of iododerma.

We presented a unique case of iododerma simulating cryptococcal infection both clinically and histopathologically. Prompt recognition of histologic mimickers of true infectious microorganisms is essential to prevent unnecessary delay of withdrawal of the offending substance and to initiate appropriate therapy.

To the Editor:

Cat scratch disease (CSD) is caused by Bartonella henselae and Bartonella clarridgeiae bacteria transferred from cats to humans that results in an inflamed inoculation site and tender lymphadenopathy. Pityriasis rosea (PR) and PR-like eruptions are self-limited, acute exanthems that have been associated with infections, vaccinations, and medications. We report a case of PR occurring in a 10-year-old girl with CSD, which may suggest an association between the 2 diseases.

A 10-year-old girl who was otherwise healthy presented in the winter with a rash of 5 days’ duration. Fourteen days prior to the rash, the patient reported being scratched by a new kitten and noted a pinpoint “puncture” on the left forearm that developed into a red papule over the following week. Seven days after the cat scratch, the patient experienced pain and swelling in the left axilla. Approximately 1 week after the onset of lymphadenopathy, the patient developed an asymptomatic rash that started with a large spot on the left chest, followed by smaller spots appearing over the next 2 days and spreading to the rest of the trunk. Four days after the rash onset, the patient experienced a mild headache, low-grade subjective fever, and chills. She denied any recent travel, bug bites, sore throat, and diarrhea. She was up-to-date on all vaccinations and had not received any vaccines preceding the symptoms. Physical examination revealed a 2-cm pink, scaly, thin plaque with a collarette of scale on the left upper chest (herald patch), along with multiple thin pink papules and small plaques with central scale on the trunk (Figure 1). A pustule with adjacent linear erosion was present on the left ventral forearm (Figure 2). The patient had a tender subcutaneous nodule in the left axilla as well as bilateral anterior and posterior cervical-chain subcutaneous tender nodules. There was no involvement of the palms, soles, or mucosae.

The patient was empirically treated for CSD with azithromycin (200 mg/5 mL), 404 mg on day 1 followed by 202 mg daily for 4 days. The rash was treated with hydrocortisone cream 2.5% twice daily for 2 weeks. A wound culture of the pustule on the left forearm was negative for neutrophils and organisms. Antibody serologies obtained 4 weeks after presentation were notable for an elevated B henselae IgG titer of 1:640, confirming the diagnosis of CSD. Following treatment with azithromycin and hydrocortisone, all of the patient’s symptoms resolved after 1 to 2 weeks.

Cat scratch disease is a zoonotic infection caused by the bacteria B henselae and the more recently described pathogen B clarridgeiae. Cat fleas spread these bacteria among cats, which subsequently inoculate the bacteria into humans through bites and scratches. The incidence of CSD in the United States is estimated to be 4.5 to 9.3 per 100,000 individuals in the outpatient setting and 0.19 to 0.86 per 100,000 individuals in the inpatient setting.¹ Geographic variance can occur based on flea populations, resulting in higher incidence in warm humid climates and lower incidence in mountainous arid climates. The incidence of CSD in the pediatric population is highest in children aged 5 to 9 years. A national representative survey (N=3011) from 2017 revealed that 37.2% of primary care providers had diagnosed CSD in the prior year.¹

Classic CSD presents as an erythematous papule at the inoculation site lasting days to weeks, with progression to tender lymphadenopathy lasting weeks to months. Fever, malaise, and chills also can be seen. Atypical CSD occurs in up to 24% of cases in immunocompetent patients.¹ Atypical and systemic presentations are varied and can include fever of unknown origin, neuroretinitis, uveitis, retinal vessel occlusion, encephalitis, hepatosplenic lesions, Parinaud oculoglandular syndrome, osteomyelitis, and endocarditis.^1,2 Atypical dermatologic presentations of CSD include maculopapular rash in 7% of cases and erythema nodosum in 2.5% of cases, as well as rare reports of cutaneous vasculitis, urticaria, immune thrombocytopenic purpura, and papuloedematous eruption.³ Treatment guidelines for CSD vary widely depending on the clinical presentation as well as the immunocompetence of the infected individual. Our patient had limited regional lymphadenopathy with no signs of dissemination or neurologic involvement and was successfully treated with a 5-day course of oral azithromycin (weight based, 10 mg/kg). More extensive disease such as hepatosplenic or neurologic CSD may require multiple antibiotics for up to 6 weeks. Alternative or additional antibiotics used for CSD include rifampin, trimethoprim-sulfamethoxazole, ciprofloxacin, doxycycline, gentamicin, and clarithromycin. Opinions vary as to whether all patients or just those with complicated infections warrant antibiotic therapy.^4-6

Pityriasis rosea is a self-limited acute exanthematous disease that is classically associated with a systemic reactivation of human herpesvirus (HHV) 6 and/or HHV-7. The incidence of PR is estimated to be 480 per 100,000 dermatologic patients. It is slightly more common in females and occurs most often in patients aged 10 to 35 years.⁷ Clinically, PR appears with the abrupt onset of a single erythematous scaly patch (termed the herald patch), followed by a secondary eruption of smaller erythematous scaly macules and patches along the trunk’s cleavage lines. The secondary eruption on the back is sometimes termed a Christmas or fir tree pattern.^7,8

In addition to the classic presentation of PR, there have been reports of numerous atypical clinical presentations. The herald patch, which classically presents on the trunk, also has been reported to present on the extremities; PR of the extremities is defined by lesions that appear as large scaly plaques on the extremities only. Inverse PR presents with lesions occurring in flexural areas and acral surfaces but not on the trunk. There also is an acral PR variant in which lesions appear only on the palms, wrists, and soles. Purpuric or hemorrhagic PR has been described and presents with purpura and petechiae with or without collarettes of scale in diffuse locations, including the palate. Oral PR presents more commonly in patients of color as erosions, ulcers, hemorrhagic lesions, bullae, or geographic tongue. Erythema multiforme–like PR appears with targetoid lesions on the trunk, face, neck, and arms without a history of herpes simplex virus infection. A large pear-shaped herald patch has been reported and characterizes the gigantea PR of Darier variant. Irritated PR occurs with typical PR findings, but afflicted patients report severe pain and burning with diaphoresis. Relapsing PR can occur within 1 year of a prior episode of PR and presents without a herald patch. Persistent PR is defined by PR lasting more than 3 months, and most reported cases have included oral lesions. Finally, other PR variants that have been described include urticarial, papular, follicular, vesicular, and hypopigmented types.^7-9

Furthermore, there have been reports of multiple atypical presentations occurring simultaneously in the same patient.¹⁰ Although PR classically has been associated with HHV-6 and/or HHV-7 reactivation, it has been reported with a few other clinical situations and conditions. Pityriasislike eruption specifically refers to an exanthem secondary to drugs or vaccination that resembles PR but shows clinical differences, including diffuse and confluent dusky-red macules and/or plaques with or without desquamation on the trunk, extremities, and face. Drugs that have been implicated as triggers include ACE inhibitors, gold, isotretinoin, nonsteroidal anti-inflammatory agents, omeprazole, terbinafine, and tyrosine kinase inhibitors. Smallpox, tuberculosis, poliomyelitis, influenza, diphtheria, tetanus, hepatitis B virus, pneumococcus, papillomavirus, yellow fever, and pertussis vaccinations also have been associated with PR.^7,11,12 Additionally, PR has been reported to occur with active systemic infections, specifically H1N1 influenza, though it is rare.¹³ Because of its self-limited course, treatment of PR most often involves only reassurance. Topical corticosteroids may be appropriate for pruritus.^7,8

Pediatric health care providers including dermatologists should be familiar with both CSD and PR because they are common diseases that more often are encountered in the pediatric population. We present a unique case of CSD presenting with concurrent PR, which highlights a potential new etiology for PR and a rare cutaneous manifestation of CSD. Further investigation into a possible relationship between CSD and PR may be warranted. Patients with any signs and symptoms of fever, tender lymphadenopathy, worsening rash, or exposure to cats warrant a thorough history and physical examination to ensure that neither entity is overlooked.

To the Editor:

Cat scratch disease (CSD) is caused by Bartonella henselae and Bartonella clarridgeiae bacteria transferred from cats to humans that results in an inflamed inoculation site and tender lymphadenopathy. Pityriasis rosea (PR) and PR-like eruptions are self-limited, acute exanthems that have been associated with infections, vaccinations, and medications. We report a case of PR occurring in a 10-year-old girl with CSD, which may suggest an association between the 2 diseases.

A 10-year-old girl who was otherwise healthy presented in the winter with a rash of 5 days’ duration. Fourteen days prior to the rash, the patient reported being scratched by a new kitten and noted a pinpoint “puncture” on the left forearm that developed into a red papule over the following week. Seven days after the cat scratch, the patient experienced pain and swelling in the left axilla. Approximately 1 week after the onset of lymphadenopathy, the patient developed an asymptomatic rash that started with a large spot on the left chest, followed by smaller spots appearing over the next 2 days and spreading to the rest of the trunk. Four days after the rash onset, the patient experienced a mild headache, low-grade subjective fever, and chills. She denied any recent travel, bug bites, sore throat, and diarrhea. She was up-to-date on all vaccinations and had not received any vaccines preceding the symptoms. Physical examination revealed a 2-cm pink, scaly, thin plaque with a collarette of scale on the left upper chest (herald patch), along with multiple thin pink papules and small plaques with central scale on the trunk (Figure 1). A pustule with adjacent linear erosion was present on the left ventral forearm (Figure 2). The patient had a tender subcutaneous nodule in the left axilla as well as bilateral anterior and posterior cervical-chain subcutaneous tender nodules. There was no involvement of the palms, soles, or mucosae.

The patient was empirically treated for CSD with azithromycin (200 mg/5 mL), 404 mg on day 1 followed by 202 mg daily for 4 days. The rash was treated with hydrocortisone cream 2.5% twice daily for 2 weeks. A wound culture of the pustule on the left forearm was negative for neutrophils and organisms. Antibody serologies obtained 4 weeks after presentation were notable for an elevated B henselae IgG titer of 1:640, confirming the diagnosis of CSD. Following treatment with azithromycin and hydrocortisone, all of the patient’s symptoms resolved after 1 to 2 weeks.

Cat scratch disease is a zoonotic infection caused by the bacteria B henselae and the more recently described pathogen B clarridgeiae. Cat fleas spread these bacteria among cats, which subsequently inoculate the bacteria into humans through bites and scratches. The incidence of CSD in the United States is estimated to be 4.5 to 9.3 per 100,000 individuals in the outpatient setting and 0.19 to 0.86 per 100,000 individuals in the inpatient setting.¹ Geographic variance can occur based on flea populations, resulting in higher incidence in warm humid climates and lower incidence in mountainous arid climates. The incidence of CSD in the pediatric population is highest in children aged 5 to 9 years. A national representative survey (N=3011) from 2017 revealed that 37.2% of primary care providers had diagnosed CSD in the prior year.¹

Classic CSD presents as an erythematous papule at the inoculation site lasting days to weeks, with progression to tender lymphadenopathy lasting weeks to months. Fever, malaise, and chills also can be seen. Atypical CSD occurs in up to 24% of cases in immunocompetent patients.¹ Atypical and systemic presentations are varied and can include fever of unknown origin, neuroretinitis, uveitis, retinal vessel occlusion, encephalitis, hepatosplenic lesions, Parinaud oculoglandular syndrome, osteomyelitis, and endocarditis.^1,2 Atypical dermatologic presentations of CSD include maculopapular rash in 7% of cases and erythema nodosum in 2.5% of cases, as well as rare reports of cutaneous vasculitis, urticaria, immune thrombocytopenic purpura, and papuloedematous eruption.³ Treatment guidelines for CSD vary widely depending on the clinical presentation as well as the immunocompetence of the infected individual. Our patient had limited regional lymphadenopathy with no signs of dissemination or neurologic involvement and was successfully treated with a 5-day course of oral azithromycin (weight based, 10 mg/kg). More extensive disease such as hepatosplenic or neurologic CSD may require multiple antibiotics for up to 6 weeks. Alternative or additional antibiotics used for CSD include rifampin, trimethoprim-sulfamethoxazole, ciprofloxacin, doxycycline, gentamicin, and clarithromycin. Opinions vary as to whether all patients or just those with complicated infections warrant antibiotic therapy.^4-6

Pityriasis rosea is a self-limited acute exanthematous disease that is classically associated with a systemic reactivation of human herpesvirus (HHV) 6 and/or HHV-7. The incidence of PR is estimated to be 480 per 100,000 dermatologic patients. It is slightly more common in females and occurs most often in patients aged 10 to 35 years.⁷ Clinically, PR appears with the abrupt onset of a single erythematous scaly patch (termed the herald patch), followed by a secondary eruption of smaller erythematous scaly macules and patches along the trunk’s cleavage lines. The secondary eruption on the back is sometimes termed a Christmas or fir tree pattern.^7,8

In addition to the classic presentation of PR, there have been reports of numerous atypical clinical presentations. The herald patch, which classically presents on the trunk, also has been reported to present on the extremities; PR of the extremities is defined by lesions that appear as large scaly plaques on the extremities only. Inverse PR presents with lesions occurring in flexural areas and acral surfaces but not on the trunk. There also is an acral PR variant in which lesions appear only on the palms, wrists, and soles. Purpuric or hemorrhagic PR has been described and presents with purpura and petechiae with or without collarettes of scale in diffuse locations, including the palate. Oral PR presents more commonly in patients of color as erosions, ulcers, hemorrhagic lesions, bullae, or geographic tongue. Erythema multiforme–like PR appears with targetoid lesions on the trunk, face, neck, and arms without a history of herpes simplex virus infection. A large pear-shaped herald patch has been reported and characterizes the gigantea PR of Darier variant. Irritated PR occurs with typical PR findings, but afflicted patients report severe pain and burning with diaphoresis. Relapsing PR can occur within 1 year of a prior episode of PR and presents without a herald patch. Persistent PR is defined by PR lasting more than 3 months, and most reported cases have included oral lesions. Finally, other PR variants that have been described include urticarial, papular, follicular, vesicular, and hypopigmented types.^7-9

Furthermore, there have been reports of multiple atypical presentations occurring simultaneously in the same patient.¹⁰ Although PR classically has been associated with HHV-6 and/or HHV-7 reactivation, it has been reported with a few other clinical situations and conditions. Pityriasislike eruption specifically refers to an exanthem secondary to drugs or vaccination that resembles PR but shows clinical differences, including diffuse and confluent dusky-red macules and/or plaques with or without desquamation on the trunk, extremities, and face. Drugs that have been implicated as triggers include ACE inhibitors, gold, isotretinoin, nonsteroidal anti-inflammatory agents, omeprazole, terbinafine, and tyrosine kinase inhibitors. Smallpox, tuberculosis, poliomyelitis, influenza, diphtheria, tetanus, hepatitis B virus, pneumococcus, papillomavirus, yellow fever, and pertussis vaccinations also have been associated with PR.^7,11,12 Additionally, PR has been reported to occur with active systemic infections, specifically H1N1 influenza, though it is rare.¹³ Because of its self-limited course, treatment of PR most often involves only reassurance. Topical corticosteroids may be appropriate for pruritus.^7,8

Pediatric health care providers including dermatologists should be familiar with both CSD and PR because they are common diseases that more often are encountered in the pediatric population. We present a unique case of CSD presenting with concurrent PR, which highlights a potential new etiology for PR and a rare cutaneous manifestation of CSD. Further investigation into a possible relationship between CSD and PR may be warranted. Patients with any signs and symptoms of fever, tender lymphadenopathy, worsening rash, or exposure to cats warrant a thorough history and physical examination to ensure that neither entity is overlooked.

To the Editor:

Cat scratch disease (CSD) is caused by Bartonella henselae and Bartonella clarridgeiae bacteria transferred from cats to humans that results in an inflamed inoculation site and tender lymphadenopathy. Pityriasis rosea (PR) and PR-like eruptions are self-limited, acute exanthems that have been associated with infections, vaccinations, and medications. We report a case of PR occurring in a 10-year-old girl with CSD, which may suggest an association between the 2 diseases.

A 10-year-old girl who was otherwise healthy presented in the winter with a rash of 5 days’ duration. Fourteen days prior to the rash, the patient reported being scratched by a new kitten and noted a pinpoint “puncture” on the left forearm that developed into a red papule over the following week. Seven days after the cat scratch, the patient experienced pain and swelling in the left axilla. Approximately 1 week after the onset of lymphadenopathy, the patient developed an asymptomatic rash that started with a large spot on the left chest, followed by smaller spots appearing over the next 2 days and spreading to the rest of the trunk. Four days after the rash onset, the patient experienced a mild headache, low-grade subjective fever, and chills. She denied any recent travel, bug bites, sore throat, and diarrhea. She was up-to-date on all vaccinations and had not received any vaccines preceding the symptoms. Physical examination revealed a 2-cm pink, scaly, thin plaque with a collarette of scale on the left upper chest (herald patch), along with multiple thin pink papules and small plaques with central scale on the trunk (Figure 1). A pustule with adjacent linear erosion was present on the left ventral forearm (Figure 2). The patient had a tender subcutaneous nodule in the left axilla as well as bilateral anterior and posterior cervical-chain subcutaneous tender nodules. There was no involvement of the palms, soles, or mucosae.

The patient was empirically treated for CSD with azithromycin (200 mg/5 mL), 404 mg on day 1 followed by 202 mg daily for 4 days. The rash was treated with hydrocortisone cream 2.5% twice daily for 2 weeks. A wound culture of the pustule on the left forearm was negative for neutrophils and organisms. Antibody serologies obtained 4 weeks after presentation were notable for an elevated B henselae IgG titer of 1:640, confirming the diagnosis of CSD. Following treatment with azithromycin and hydrocortisone, all of the patient’s symptoms resolved after 1 to 2 weeks.

Cat scratch disease is a zoonotic infection caused by the bacteria B henselae and the more recently described pathogen B clarridgeiae. Cat fleas spread these bacteria among cats, which subsequently inoculate the bacteria into humans through bites and scratches. The incidence of CSD in the United States is estimated to be 4.5 to 9.3 per 100,000 individuals in the outpatient setting and 0.19 to 0.86 per 100,000 individuals in the inpatient setting.¹ Geographic variance can occur based on flea populations, resulting in higher incidence in warm humid climates and lower incidence in mountainous arid climates. The incidence of CSD in the pediatric population is highest in children aged 5 to 9 years. A national representative survey (N=3011) from 2017 revealed that 37.2% of primary care providers had diagnosed CSD in the prior year.¹

Classic CSD presents as an erythematous papule at the inoculation site lasting days to weeks, with progression to tender lymphadenopathy lasting weeks to months. Fever, malaise, and chills also can be seen. Atypical CSD occurs in up to 24% of cases in immunocompetent patients.¹ Atypical and systemic presentations are varied and can include fever of unknown origin, neuroretinitis, uveitis, retinal vessel occlusion, encephalitis, hepatosplenic lesions, Parinaud oculoglandular syndrome, osteomyelitis, and endocarditis.^1,2 Atypical dermatologic presentations of CSD include maculopapular rash in 7% of cases and erythema nodosum in 2.5% of cases, as well as rare reports of cutaneous vasculitis, urticaria, immune thrombocytopenic purpura, and papuloedematous eruption.³ Treatment guidelines for CSD vary widely depending on the clinical presentation as well as the immunocompetence of the infected individual. Our patient had limited regional lymphadenopathy with no signs of dissemination or neurologic involvement and was successfully treated with a 5-day course of oral azithromycin (weight based, 10 mg/kg). More extensive disease such as hepatosplenic or neurologic CSD may require multiple antibiotics for up to 6 weeks. Alternative or additional antibiotics used for CSD include rifampin, trimethoprim-sulfamethoxazole, ciprofloxacin, doxycycline, gentamicin, and clarithromycin. Opinions vary as to whether all patients or just those with complicated infections warrant antibiotic therapy.^4-6

Pityriasis rosea is a self-limited acute exanthematous disease that is classically associated with a systemic reactivation of human herpesvirus (HHV) 6 and/or HHV-7. The incidence of PR is estimated to be 480 per 100,000 dermatologic patients. It is slightly more common in females and occurs most often in patients aged 10 to 35 years.⁷ Clinically, PR appears with the abrupt onset of a single erythematous scaly patch (termed the herald patch), followed by a secondary eruption of smaller erythematous scaly macules and patches along the trunk’s cleavage lines. The secondary eruption on the back is sometimes termed a Christmas or fir tree pattern.^7,8

In addition to the classic presentation of PR, there have been reports of numerous atypical clinical presentations. The herald patch, which classically presents on the trunk, also has been reported to present on the extremities; PR of the extremities is defined by lesions that appear as large scaly plaques on the extremities only. Inverse PR presents with lesions occurring in flexural areas and acral surfaces but not on the trunk. There also is an acral PR variant in which lesions appear only on the palms, wrists, and soles. Purpuric or hemorrhagic PR has been described and presents with purpura and petechiae with or without collarettes of scale in diffuse locations, including the palate. Oral PR presents more commonly in patients of color as erosions, ulcers, hemorrhagic lesions, bullae, or geographic tongue. Erythema multiforme–like PR appears with targetoid lesions on the trunk, face, neck, and arms without a history of herpes simplex virus infection. A large pear-shaped herald patch has been reported and characterizes the gigantea PR of Darier variant. Irritated PR occurs with typical PR findings, but afflicted patients report severe pain and burning with diaphoresis. Relapsing PR can occur within 1 year of a prior episode of PR and presents without a herald patch. Persistent PR is defined by PR lasting more than 3 months, and most reported cases have included oral lesions. Finally, other PR variants that have been described include urticarial, papular, follicular, vesicular, and hypopigmented types.^7-9

Furthermore, there have been reports of multiple atypical presentations occurring simultaneously in the same patient.¹⁰ Although PR classically has been associated with HHV-6 and/or HHV-7 reactivation, it has been reported with a few other clinical situations and conditions. Pityriasislike eruption specifically refers to an exanthem secondary to drugs or vaccination that resembles PR but shows clinical differences, including diffuse and confluent dusky-red macules and/or plaques with or without desquamation on the trunk, extremities, and face. Drugs that have been implicated as triggers include ACE inhibitors, gold, isotretinoin, nonsteroidal anti-inflammatory agents, omeprazole, terbinafine, and tyrosine kinase inhibitors. Smallpox, tuberculosis, poliomyelitis, influenza, diphtheria, tetanus, hepatitis B virus, pneumococcus, papillomavirus, yellow fever, and pertussis vaccinations also have been associated with PR.^7,11,12 Additionally, PR has been reported to occur with active systemic infections, specifically H1N1 influenza, though it is rare.¹³ Because of its self-limited course, treatment of PR most often involves only reassurance. Topical corticosteroids may be appropriate for pruritus.^7,8

Pediatric health care providers including dermatologists should be familiar with both CSD and PR because they are common diseases that more often are encountered in the pediatric population. We present a unique case of CSD presenting with concurrent PR, which highlights a potential new etiology for PR and a rare cutaneous manifestation of CSD. Further investigation into a possible relationship between CSD and PR may be warranted. Patients with any signs and symptoms of fever, tender lymphadenopathy, worsening rash, or exposure to cats warrant a thorough history and physical examination to ensure that neither entity is overlooked.

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

To the Editor:

The term ectopic breast tissue serves as an umbrella term that encompasses breast tissue positioned in anatomically incorrect locations, including the subtypes of supernumerary and aberrant breasts.¹ However, the more frequently used term is accessory breast tissue (ABT).¹ Supernumerary breasts have diverse variations of a nipple, areola, and/or ductal tissue and can span in size from a small mole to a fully functioning breast. This breast type maintains structured ductal systems connected to the overlying skin and experiences regular changes during the reproductive cycle. In contrast, an aberrant breast is isolated breast tissue that does not contain organized ductal systems.¹ Accessory breast tissue is prevalent in up to 6.0% of the world population, with Japanese individuals being the most affected and White individuals being the least affected.¹

Accessory breasts typically are located along the milk line—the embryologic precursor to mammary glands and nipples, which extend from the axillae to the groin and regress from the caudal end spanning to the groin.² For this reason, incomplete regression of the mammary ridge results in ABT, most commonly in the axillary region.³ Accessory breast tissue usually is benign and is considered an anatomical variant; however, because the histomorphology is similar to mammary gland tissue, accessory breasts have the same proliferative potential as anatomically correct breasts and therefore can form fibroadenomas, cysts, abscesses, mastitis, or breast cancer.⁴ Accessory breast carcinomas comprise 0.3% to 0.6% of all breast malignancies.⁵ Certain genodermatoses (ie, Cowden syndrome) also may predispose patients to benign or malignant pathology in ABT.⁶ We present a rare case of accessory breast cancer in the inframammary region masquerading as a cyst. These findings were further supported by ultrasonography and mammography.

A 45-year-old White woman presented to our clinic for removal of a dermal mass underlying a supernumerary nipple at the left inframammary fold. Her medical history was noncontributory and was only remarkable for uterine fibroids. She developed pain and swelling in the left breast 1 year prior, which prompted her to seek medical attention from her primary care physician. Diagnostic mammography was negative for any concerning malignant nodules, and subsequent BRCA genetic testing also was negative. Six months after the diagnostic mammography, she continued to experience pain and swelling in the left breast and was then referred for diagnostic ultrasonography; 2 masses in the left breast suspected as infected cysts with rupture were identified (Figure 1). She was then referred to our dermatology clinic for evaluation and surgical extirpation of the suspected cyst underlying the accessory breast. The area subsequently was excised under local anesthesia, and a second similar but smaller mass also was identified adjacent to the initial growth. Dermatopathologic examination revealed an estrogen receptor– (Figure 2A) and progesterone receptor–positive (Figure 2B), ERBB2 (HER2/neu)–negative, nuclear grade III ductal carcinoma in situ (Figure 3).

Various ABT classification methods have been proposed with Brightmore⁷ categorizing polymastia into 8 subtypes: (1) complete breast; (2) glandular tissue and nipple; (3) glandular tissue and areola; (4) glandular tissue only; (5) nipple, areola, and fat; (6) nipple only; (7) areola only; and (8) patch of hair only. De Cholnokey⁸ focused on axillary polymastia, dividing it into 4 classes: (1) axillary tumor in milk line without nipple or areola; (2) axillary tumor with areola with or without pigmentation; (3) nipple or areola without underlying breast tissue; and (4) complete breast with nipple, areola, and glandular tissue. Fenench’s⁹ method is preferred and simply describes ABT as 2 subtypes: supernumerary and aberrant.^1,2,10 One study observed 6% of ABT cancers were the supernumerary type and 94% were the aberrant type.¹ Ductal lumen stagnation increases the risk for accessory breast carcinoma development.¹⁰ Men have a higher prevalence of cancer in ABT compared to anatomically correct breast tissue.¹¹

There currently is no standardized guideline for ABT cancer treatment. The initial clinical impression of cancer of ABT may be misdiagnosed as lymphadenopathy, abscesses, or lipomas.¹² The risk for misdiagnosis is higher for cancer of ABT compared to normal breast tissue and is associated with a poorer prognosis.¹ Despite multiple screening modalities, our patient’s initial breast cancer screenings proved unreliable. A mammogram failed to detect malignancy, likely secondary to the area of concern being out of the standard imaging field. Ultrasonography also was unreliable and led to misdiagnosis as an infected sebaceous cyst with rupture in our patient. Upon review of the ultrasound, concerns were raised by dermatology that the mass was more likely an epidermal inclusion cyst with rupture given the more superficial and sac-free nature of sebaceous cysts, which commonly are associated with steatocystoma multiplex.¹³ Definitive diagnosis of ductal carcinoma in situ was made with dermatopathologic examination.

Prophylactic surgical excision of ABT has been recommended, suggesting that excisional biopsy and histopathologic examination is the more appropriate method to rule out malignancy. Surgical treatment of ABT may omit any risk for malignant transformation and may provide psychological relief to patients for aesthetic reasons.^10,12,14 The risk and benefits of prophylactic excision of ABT has been compared to prophylactic mastectomy of anatomically correct breasts,¹⁵ with some clinicians considering this definitive procedure unnecessary except in high-risk patients with a strong genetic predisposition.^16,17

Accessory breast tissue should be viewed as an anatomical variant with the option of surgical removal for symptomatic concerns, such as firm nodules, discharge, and pain. Although ABT is rare and cancer in ABT is even more uncommon (<1% of all breast cancers),^5,11 clinicians should be suspicious of benign diagnostic reports when the clinical situation does not fit the proposed narrative.

To the Editor:

Palifermin is a recombinant keratinocyte growth factor (KGF) approved by the US Food and Drug Administration to prevent oral mucositis following radiation therapy or chemotherapy. Cutaneous reactions associated with palifermin have been reported.^1-5 One case described a distinctive polymorphous eruption in a patient treated with palifermin.⁶ On histologic analysis, papules demonstrated findings similar to verrucae, with evidence of papillomatosis, hypergranulosis, and hyperorthokeratosis. Given its mechanism of action as a KGF, it was concluded that these findings were likely the direct result of palifermin.⁶ We report a similar case of a patient who was given palifermin prior to an autologous stem cell transplant. Histopathologic analysis confirmed epidermal dysmaturation and marked hypergranulosis. We present this case to expand the paucity of data on palifermin-associated cutaneous reactions.

A 63-year-old man with a history of psoriasis, eczema, and relapsed diffuse large B-cell lymphoma was admitted to the hospital for routine management of an autologous stem cell transplant with a conditioning regimen involving thiotepa, busulfan, and cyclophosphamide. The patient had completed a 3-day course of palifermin 1 day prior to the current presentation. On admission, he developed a pruritic erythematous rash over the face and axillae. Within 24 hours, the facial rash progressed with appreciable edema, and he reported difficulty opening his eyes. He denied any fever, nausea, vomiting, diarrhea, or increased fatigue. He also denied use of any other medications other than starting a course of prophylactic trimethoprim-sulfamethoxazole 3 times weekly 2 months prior to admission.

Diffuse blanching erythema with a well-demarcated linear border was noted along the lower anterior neck extending to the posterior hairline. There was notable edema but no evidence of pustules or overlying scale. Similar areas of blanchable erythema were present along the axillae and inguinal folds. There also were flesh-colored to pink papules within the axillary vaults and on the back that occasionally coalesced into plaques. There was no involvement of the mucous membranes or acral sites.

A complete blood cell count with differential and a comprehensive metabolic profile largely were unremarkable. A potassium hydroxide preparation of the face and groin was negative for hyphae and Demodex mites. Histopathologic analysis from a punch biopsy of a representative papule from the posterior neck demonstrated epidermal dysmaturation with marked thickening of the granular cell layer with notably large keratohyalin granules (Figure 1).

In the setting of treatment with thiotepa, we recommended supportive care with cool compresses rather than topical medication because he was neutropenic, and we wanted to avoid further immunosuppression or toxicity. By 24 hours after completing the course of palifermin, the patient experienced complete resolution of the rash. At his request, the trial of palifermin was restarted 10 days into conditioning therapy. A similar rash with less facial edema but more prominent involvement of the chest appeared 3 days into the retrial (Figure 2). The medication was discontinued, which resulted in resolution of the rash. Again, the patient remained afebrile without involvement of the mucous membranes. Liver enzyme and creatinine levels remained within reference range.Eosinophilia and the level of atypical lymphocytes could not be assessed because of leukopenia in the setting of recent chemotherapy. The rash self-resolved in 4 days.

Palifermin is a recombinant form of human KGF that is more stable than the endogenous form but retains all vital properties of the protein.^5-7 Similar to other growth factors, KGF induces differentiation, proliferation, and migration of cells in vivo.⁸ However, it uniquely produces a targeted effect on epithelial cells in the skin, oral mucosa, lungs, gastrointestinal tract, and genitourinary system.^7-9

Palifermin was approved by the US Food and Drug Administration in 2004 for the prevention and treatment of severe oral mucositis in patients receiving myelotoxic therapy prior to stem cell transplantation.^7,9 Severe mucositis occurs in approximately 70% to 80% of patients receiving radiation or chemotherapy-based conditioning treatments.^4,7 Compared to placebo, palifermin has been shown to greatly reduce the incidence of Grade 4 oral mucositis, defined as severe enough to prevent alimentation.¹⁰

The proliferative effect of palifermin on the oral mucosa is beneficial to patients but likely is the driving force behind its cutaneous adverse effects. A nonspecific rash is the most commonly cited treatment-related adverse event associated with palifermin, occurring in approximately 62% of patients.^5,7,9

Our case is a rare report of a palifermin-associated cutaneous reaction. Previous cases have cited the occurrence of palmoplantar erythrodysesthesias, papulopustular eruptions involving the face and chest, and a papular rash involving the dorsal hands and intertriginous areas.^1-4 Another report documented a “mild rash” but failed to further characterize the morphology or the body site involved.⁵

In 2009, King et al⁶ reported the occurrence of a lichen planus–like eruption involving the intertriginous regions and of white oral plaques in a patient treated with palifermin. Hematoxylin and eosin staining of a representative lesion in that patient demonstrated an appearance similar to that of verrucae, including papillomatosis, hypergranulosis, and hyperorthokeratosis.

King et al⁶ expanded analysis of the reaction to include immunohistochemical study, using targeted antibody stains for cytokeratin 5/6 and Ki-67 protein. Staining with Ki-67 showed dramatically increased activity within basilar and suprabasilar keratinocytes in a biopsy taken at the height of the reaction. Biopsy specimens obtained when the eruption was clinically resolving—2 days after the first biopsy—showed decreased Ki-67 staining. These findings taken together suggest a direct causal effect of palifermin inducing hyperkeratotic changes appreciated on examination of treated patients.⁶

We present this case to add to current data regarding palifermin-induced cutaneous changes. Unique to our patient was a strikingly well-demarcated rash confined to the head and neck. Although a photosensitive eruption due to trimethoprim-sulfamethoxazole is conceivable, the fixed time course of the eruption—corresponding to (1) initiation and discontinuation of palifermin and (2) histologic findings—led us to conclude that this self-limited eruption likely was due to palifermin.

To the Editor:

Palifermin is a recombinant keratinocyte growth factor (KGF) approved by the US Food and Drug Administration to prevent oral mucositis following radiation therapy or chemotherapy. Cutaneous reactions associated with palifermin have been reported.^1-5 One case described a distinctive polymorphous eruption in a patient treated with palifermin.⁶ On histologic analysis, papules demonstrated findings similar to verrucae, with evidence of papillomatosis, hypergranulosis, and hyperorthokeratosis. Given its mechanism of action as a KGF, it was concluded that these findings were likely the direct result of palifermin.⁶ We report a similar case of a patient who was given palifermin prior to an autologous stem cell transplant. Histopathologic analysis confirmed epidermal dysmaturation and marked hypergranulosis. We present this case to expand the paucity of data on palifermin-associated cutaneous reactions.

A 63-year-old man with a history of psoriasis, eczema, and relapsed diffuse large B-cell lymphoma was admitted to the hospital for routine management of an autologous stem cell transplant with a conditioning regimen involving thiotepa, busulfan, and cyclophosphamide. The patient had completed a 3-day course of palifermin 1 day prior to the current presentation. On admission, he developed a pruritic erythematous rash over the face and axillae. Within 24 hours, the facial rash progressed with appreciable edema, and he reported difficulty opening his eyes. He denied any fever, nausea, vomiting, diarrhea, or increased fatigue. He also denied use of any other medications other than starting a course of prophylactic trimethoprim-sulfamethoxazole 3 times weekly 2 months prior to admission.

Diffuse blanching erythema with a well-demarcated linear border was noted along the lower anterior neck extending to the posterior hairline. There was notable edema but no evidence of pustules or overlying scale. Similar areas of blanchable erythema were present along the axillae and inguinal folds. There also were flesh-colored to pink papules within the axillary vaults and on the back that occasionally coalesced into plaques. There was no involvement of the mucous membranes or acral sites.

A complete blood cell count with differential and a comprehensive metabolic profile largely were unremarkable. A potassium hydroxide preparation of the face and groin was negative for hyphae and Demodex mites. Histopathologic analysis from a punch biopsy of a representative papule from the posterior neck demonstrated epidermal dysmaturation with marked thickening of the granular cell layer with notably large keratohyalin granules (Figure 1).

In the setting of treatment with thiotepa, we recommended supportive care with cool compresses rather than topical medication because he was neutropenic, and we wanted to avoid further immunosuppression or toxicity. By 24 hours after completing the course of palifermin, the patient experienced complete resolution of the rash. At his request, the trial of palifermin was restarted 10 days into conditioning therapy. A similar rash with less facial edema but more prominent involvement of the chest appeared 3 days into the retrial (Figure 2). The medication was discontinued, which resulted in resolution of the rash. Again, the patient remained afebrile without involvement of the mucous membranes. Liver enzyme and creatinine levels remained within reference range.Eosinophilia and the level of atypical lymphocytes could not be assessed because of leukopenia in the setting of recent chemotherapy. The rash self-resolved in 4 days.

Palifermin is a recombinant form of human KGF that is more stable than the endogenous form but retains all vital properties of the protein.^5-7 Similar to other growth factors, KGF induces differentiation, proliferation, and migration of cells in vivo.⁸ However, it uniquely produces a targeted effect on epithelial cells in the skin, oral mucosa, lungs, gastrointestinal tract, and genitourinary system.^7-9

Palifermin was approved by the US Food and Drug Administration in 2004 for the prevention and treatment of severe oral mucositis in patients receiving myelotoxic therapy prior to stem cell transplantation.^7,9 Severe mucositis occurs in approximately 70% to 80% of patients receiving radiation or chemotherapy-based conditioning treatments.^4,7 Compared to placebo, palifermin has been shown to greatly reduce the incidence of Grade 4 oral mucositis, defined as severe enough to prevent alimentation.¹⁰

The proliferative effect of palifermin on the oral mucosa is beneficial to patients but likely is the driving force behind its cutaneous adverse effects. A nonspecific rash is the most commonly cited treatment-related adverse event associated with palifermin, occurring in approximately 62% of patients.^5,7,9

Our case is a rare report of a palifermin-associated cutaneous reaction. Previous cases have cited the occurrence of palmoplantar erythrodysesthesias, papulopustular eruptions involving the face and chest, and a papular rash involving the dorsal hands and intertriginous areas.^1-4 Another report documented a “mild rash” but failed to further characterize the morphology or the body site involved.⁵

In 2009, King et al⁶ reported the occurrence of a lichen planus–like eruption involving the intertriginous regions and of white oral plaques in a patient treated with palifermin. Hematoxylin and eosin staining of a representative lesion in that patient demonstrated an appearance similar to that of verrucae, including papillomatosis, hypergranulosis, and hyperorthokeratosis.

King et al⁶ expanded analysis of the reaction to include immunohistochemical study, using targeted antibody stains for cytokeratin 5/6 and Ki-67 protein. Staining with Ki-67 showed dramatically increased activity within basilar and suprabasilar keratinocytes in a biopsy taken at the height of the reaction. Biopsy specimens obtained when the eruption was clinically resolving—2 days after the first biopsy—showed decreased Ki-67 staining. These findings taken together suggest a direct causal effect of palifermin inducing hyperkeratotic changes appreciated on examination of treated patients.⁶

We present this case to add to current data regarding palifermin-induced cutaneous changes. Unique to our patient was a strikingly well-demarcated rash confined to the head and neck. Although a photosensitive eruption due to trimethoprim-sulfamethoxazole is conceivable, the fixed time course of the eruption—corresponding to (1) initiation and discontinuation of palifermin and (2) histologic findings—led us to conclude that this self-limited eruption likely was due to palifermin.

To the Editor:

Palifermin is a recombinant keratinocyte growth factor (KGF) approved by the US Food and Drug Administration to prevent oral mucositis following radiation therapy or chemotherapy. Cutaneous reactions associated with palifermin have been reported.^1-5 One case described a distinctive polymorphous eruption in a patient treated with palifermin.⁶ On histologic analysis, papules demonstrated findings similar to verrucae, with evidence of papillomatosis, hypergranulosis, and hyperorthokeratosis. Given its mechanism of action as a KGF, it was concluded that these findings were likely the direct result of palifermin.⁶ We report a similar case of a patient who was given palifermin prior to an autologous stem cell transplant. Histopathologic analysis confirmed epidermal dysmaturation and marked hypergranulosis. We present this case to expand the paucity of data on palifermin-associated cutaneous reactions.

A 63-year-old man with a history of psoriasis, eczema, and relapsed diffuse large B-cell lymphoma was admitted to the hospital for routine management of an autologous stem cell transplant with a conditioning regimen involving thiotepa, busulfan, and cyclophosphamide. The patient had completed a 3-day course of palifermin 1 day prior to the current presentation. On admission, he developed a pruritic erythematous rash over the face and axillae. Within 24 hours, the facial rash progressed with appreciable edema, and he reported difficulty opening his eyes. He denied any fever, nausea, vomiting, diarrhea, or increased fatigue. He also denied use of any other medications other than starting a course of prophylactic trimethoprim-sulfamethoxazole 3 times weekly 2 months prior to admission.

Diffuse blanching erythema with a well-demarcated linear border was noted along the lower anterior neck extending to the posterior hairline. There was notable edema but no evidence of pustules or overlying scale. Similar areas of blanchable erythema were present along the axillae and inguinal folds. There also were flesh-colored to pink papules within the axillary vaults and on the back that occasionally coalesced into plaques. There was no involvement of the mucous membranes or acral sites.

A complete blood cell count with differential and a comprehensive metabolic profile largely were unremarkable. A potassium hydroxide preparation of the face and groin was negative for hyphae and Demodex mites. Histopathologic analysis from a punch biopsy of a representative papule from the posterior neck demonstrated epidermal dysmaturation with marked thickening of the granular cell layer with notably large keratohyalin granules (Figure 1).

In the setting of treatment with thiotepa, we recommended supportive care with cool compresses rather than topical medication because he was neutropenic, and we wanted to avoid further immunosuppression or toxicity. By 24 hours after completing the course of palifermin, the patient experienced complete resolution of the rash. At his request, the trial of palifermin was restarted 10 days into conditioning therapy. A similar rash with less facial edema but more prominent involvement of the chest appeared 3 days into the retrial (Figure 2). The medication was discontinued, which resulted in resolution of the rash. Again, the patient remained afebrile without involvement of the mucous membranes. Liver enzyme and creatinine levels remained within reference range.Eosinophilia and the level of atypical lymphocytes could not be assessed because of leukopenia in the setting of recent chemotherapy. The rash self-resolved in 4 days.

Palifermin is a recombinant form of human KGF that is more stable than the endogenous form but retains all vital properties of the protein.^5-7 Similar to other growth factors, KGF induces differentiation, proliferation, and migration of cells in vivo.⁸ However, it uniquely produces a targeted effect on epithelial cells in the skin, oral mucosa, lungs, gastrointestinal tract, and genitourinary system.^7-9

Palifermin was approved by the US Food and Drug Administration in 2004 for the prevention and treatment of severe oral mucositis in patients receiving myelotoxic therapy prior to stem cell transplantation.^7,9 Severe mucositis occurs in approximately 70% to 80% of patients receiving radiation or chemotherapy-based conditioning treatments.^4,7 Compared to placebo, palifermin has been shown to greatly reduce the incidence of Grade 4 oral mucositis, defined as severe enough to prevent alimentation.¹⁰

The proliferative effect of palifermin on the oral mucosa is beneficial to patients but likely is the driving force behind its cutaneous adverse effects. A nonspecific rash is the most commonly cited treatment-related adverse event associated with palifermin, occurring in approximately 62% of patients.^5,7,9

Our case is a rare report of a palifermin-associated cutaneous reaction. Previous cases have cited the occurrence of palmoplantar erythrodysesthesias, papulopustular eruptions involving the face and chest, and a papular rash involving the dorsal hands and intertriginous areas.^1-4 Another report documented a “mild rash” but failed to further characterize the morphology or the body site involved.⁵

In 2009, King et al⁶ reported the occurrence of a lichen planus–like eruption involving the intertriginous regions and of white oral plaques in a patient treated with palifermin. Hematoxylin and eosin staining of a representative lesion in that patient demonstrated an appearance similar to that of verrucae, including papillomatosis, hypergranulosis, and hyperorthokeratosis.

King et al⁶ expanded analysis of the reaction to include immunohistochemical study, using targeted antibody stains for cytokeratin 5/6 and Ki-67 protein. Staining with Ki-67 showed dramatically increased activity within basilar and suprabasilar keratinocytes in a biopsy taken at the height of the reaction. Biopsy specimens obtained when the eruption was clinically resolving—2 days after the first biopsy—showed decreased Ki-67 staining. These findings taken together suggest a direct causal effect of palifermin inducing hyperkeratotic changes appreciated on examination of treated patients.⁶

We present this case to add to current data regarding palifermin-induced cutaneous changes. Unique to our patient was a strikingly well-demarcated rash confined to the head and neck. Although a photosensitive eruption due to trimethoprim-sulfamethoxazole is conceivable, the fixed time course of the eruption—corresponding to (1) initiation and discontinuation of palifermin and (2) histologic findings—led us to conclude that this self-limited eruption likely was due to palifermin.

To the Editor:

Alopecia areata (AA) is an autoimmune nonscarring hair loss disorder that can present at any age. Patients with AA have a disproportionately high comorbidity burden and low quality of life, often grappling with anxiety, depression, and psychosocial sequelae involving identity, such as reduced self-esteem.^1,2 Although conventional therapies aim to reduce hair loss, none are curative.³ Response to treatment is highly unpredictable, with current data suggesting that up to 50% of patients recover within 1 year while 14% to 25% progress to either alopecia totalis (total scalp hair loss) or alopecia universalis (total body hair loss).⁴ Options for therapeutic intervention remain limited and vary in safety and effectiveness, warranting further research to identify optimal modalities and minimize side effects. Interestingly, scalp rolling has been used as an adjuvant to topical triamcinolone acetonide.^3,5 However, the extent of its effect in combination with other therapies remains unclear. We report 3 pediatric patients with confirmed AA refractory to conventional topical treatment who experienced remarkable scalp hair regrowth after adding biweekly scalp rolling as an adjuvant therapy.

A 7-year-old boy with AA presented with 95% scalp hair loss of 7 months’ duration (Figure 1A)(patient 1). Prior treatments included mometasone solution and clobetasol solution 0.05%. After 3 months of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth after 13 months of treatment (Figure 1B). No pain, bleeding, or other side effects were reported.

An 11-year-old girl with AA presented with 100% hair loss of 7 months’ duration (Figure 2A)(patient 2). Prior treatments included fluocinonide solution and intralesional Kenalog injections. After 4 months of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth after 13 months of treatment (Figure 2B). No pain, bleeding, or other side effects were reported.

A 16-year-old boy with AA presented with 30% hair loss of 4 years’ duration (Figure 3A)(patient 3). Prior treatments included squaric acid and intralesional Kenalog injections. After 2 years of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth at 17 months (Figure 3B). No pain, bleeding, or other side effects were reported.

Scalp rolling—also known as microneedling—provides a multifactorial approach to hair regrowth in patients with AA. The mechanism of action involves both the hair cycle and wound repair pathways by stimulation of the dermal papillae and stem cells.⁶ Scalp rolling has been observed to induce the expression of several hair growth pathway mediators, such as WNT3A, β-catenin, vascular endothelial growth factor, and WNT10B.⁷ Wnt/β-catenin pathway signaling is integral to multiple aspects of the hair regrowth process, including hair morphogenesis, follicle regeneration, and growth of the shaft itself.^8,9 Scalp rolling causes microinjuries to the skin, thereby diverting blood supply to the follicles and stimulating wound regeneration, a process suggested to induce follicle regeneration. This effect is due to increased expression of vascular endothelial growth factor after cutaneous injury, a mediator of both hair growth and cycling as well as wound repair.⁷ Adjuvant scalp rolling creates a synergistic effect by facilitating absorption of topical and intralesional therapies. The physical breakdown of dermal capillary barriers creates microchannels that traverse the stratum corneum, improving the permeability of small-molecule substances and allowing for relatively painless and uniform delivery of combination therapies. A secondary benefit is hypertrophy, which counteracts the atrophy caused by topical steroids via collagen induction.⁷

Additionally, scalp rolling confers minimal risk to the patient, making it safer than conventional pharmacologic therapies such as corticosteroids or Janus kinase (JAK) inhibitors. Although intralesional steroid injections are first-line treatments for limited disease, they can cause pain and skin atrophy.¹⁰ In one cohort of 54 patients, topical steroids were inferior to both oral and intralesional treatment, and oral steroids carried a systemic side-effect profile and worsening of comorbidities including hyperglycemia and hypertension as well as negative effects on bone density.¹¹ Baricitinib, a JAK inhibitor, was the first systemic treatment to gain US Food and Drug Administration approval for severe AA.¹² However, this novel therapeutic confers adverse effects including infection, acne, and hypercholesterolemia, as reported in the BRAVE-AA trials.¹³ More broadly, the US Food and Drug Administration warns of serious long-term risks such as cardiovascular events and malignancy.¹⁴ Given the tremendous potential of JAK inhibitors, further research is warranted to understand both the efficacy of topical formulations as well as the possible role of scalp rolling as its adjuvant.

Finally, scalp rolling is easily accessible and affordable to patients. Scalp rolling devices are readily available and affordable online, and they can be used autonomously at home. This pragmatic option allows patients to take control of their own treatment course and offers a financially feasible alternative to navigating insurance coverage as well as the need for extra office visits for medication refills and monitoring.

We report 3 cases of the use of scalp rolling as an adjuvant to conventional therapy for refractory AA in young patients. Although prospective research is required to establish causality and characterize age-related trends in treatment response, consideration of scalp rolling as an adjuvant to conventional therapy may help to optimize treatment regimens. Given its low risk for side effects and potential benefits, we recommend scalp rolling for patients with refractory AA.

To the Editor:

Alopecia areata (AA) is an autoimmune nonscarring hair loss disorder that can present at any age. Patients with AA have a disproportionately high comorbidity burden and low quality of life, often grappling with anxiety, depression, and psychosocial sequelae involving identity, such as reduced self-esteem.^1,2 Although conventional therapies aim to reduce hair loss, none are curative.³ Response to treatment is highly unpredictable, with current data suggesting that up to 50% of patients recover within 1 year while 14% to 25% progress to either alopecia totalis (total scalp hair loss) or alopecia universalis (total body hair loss).⁴ Options for therapeutic intervention remain limited and vary in safety and effectiveness, warranting further research to identify optimal modalities and minimize side effects. Interestingly, scalp rolling has been used as an adjuvant to topical triamcinolone acetonide.^3,5 However, the extent of its effect in combination with other therapies remains unclear. We report 3 pediatric patients with confirmed AA refractory to conventional topical treatment who experienced remarkable scalp hair regrowth after adding biweekly scalp rolling as an adjuvant therapy.

A 7-year-old boy with AA presented with 95% scalp hair loss of 7 months’ duration (Figure 1A)(patient 1). Prior treatments included mometasone solution and clobetasol solution 0.05%. After 3 months of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth after 13 months of treatment (Figure 1B). No pain, bleeding, or other side effects were reported.

An 11-year-old girl with AA presented with 100% hair loss of 7 months’ duration (Figure 2A)(patient 2). Prior treatments included fluocinonide solution and intralesional Kenalog injections. After 4 months of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth after 13 months of treatment (Figure 2B). No pain, bleeding, or other side effects were reported.

A 16-year-old boy with AA presented with 30% hair loss of 4 years’ duration (Figure 3A)(patient 3). Prior treatments included squaric acid and intralesional Kenalog injections. After 2 years of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth at 17 months (Figure 3B). No pain, bleeding, or other side effects were reported.

Scalp rolling—also known as microneedling—provides a multifactorial approach to hair regrowth in patients with AA. The mechanism of action involves both the hair cycle and wound repair pathways by stimulation of the dermal papillae and stem cells.⁶ Scalp rolling has been observed to induce the expression of several hair growth pathway mediators, such as WNT3A, β-catenin, vascular endothelial growth factor, and WNT10B.⁷ Wnt/β-catenin pathway signaling is integral to multiple aspects of the hair regrowth process, including hair morphogenesis, follicle regeneration, and growth of the shaft itself.^8,9 Scalp rolling causes microinjuries to the skin, thereby diverting blood supply to the follicles and stimulating wound regeneration, a process suggested to induce follicle regeneration. This effect is due to increased expression of vascular endothelial growth factor after cutaneous injury, a mediator of both hair growth and cycling as well as wound repair.⁷ Adjuvant scalp rolling creates a synergistic effect by facilitating absorption of topical and intralesional therapies. The physical breakdown of dermal capillary barriers creates microchannels that traverse the stratum corneum, improving the permeability of small-molecule substances and allowing for relatively painless and uniform delivery of combination therapies. A secondary benefit is hypertrophy, which counteracts the atrophy caused by topical steroids via collagen induction.⁷

Additionally, scalp rolling confers minimal risk to the patient, making it safer than conventional pharmacologic therapies such as corticosteroids or Janus kinase (JAK) inhibitors. Although intralesional steroid injections are first-line treatments for limited disease, they can cause pain and skin atrophy.¹⁰ In one cohort of 54 patients, topical steroids were inferior to both oral and intralesional treatment, and oral steroids carried a systemic side-effect profile and worsening of comorbidities including hyperglycemia and hypertension as well as negative effects on bone density.¹¹ Baricitinib, a JAK inhibitor, was the first systemic treatment to gain US Food and Drug Administration approval for severe AA.¹² However, this novel therapeutic confers adverse effects including infection, acne, and hypercholesterolemia, as reported in the BRAVE-AA trials.¹³ More broadly, the US Food and Drug Administration warns of serious long-term risks such as cardiovascular events and malignancy.¹⁴ Given the tremendous potential of JAK inhibitors, further research is warranted to understand both the efficacy of topical formulations as well as the possible role of scalp rolling as its adjuvant.

Finally, scalp rolling is easily accessible and affordable to patients. Scalp rolling devices are readily available and affordable online, and they can be used autonomously at home. This pragmatic option allows patients to take control of their own treatment course and offers a financially feasible alternative to navigating insurance coverage as well as the need for extra office visits for medication refills and monitoring.

We report 3 cases of the use of scalp rolling as an adjuvant to conventional therapy for refractory AA in young patients. Although prospective research is required to establish causality and characterize age-related trends in treatment response, consideration of scalp rolling as an adjuvant to conventional therapy may help to optimize treatment regimens. Given its low risk for side effects and potential benefits, we recommend scalp rolling for patients with refractory AA.

To the Editor:

Alopecia areata (AA) is an autoimmune nonscarring hair loss disorder that can present at any age. Patients with AA have a disproportionately high comorbidity burden and low quality of life, often grappling with anxiety, depression, and psychosocial sequelae involving identity, such as reduced self-esteem.^1,2 Although conventional therapies aim to reduce hair loss, none are curative.³ Response to treatment is highly unpredictable, with current data suggesting that up to 50% of patients recover within 1 year while 14% to 25% progress to either alopecia totalis (total scalp hair loss) or alopecia universalis (total body hair loss).⁴ Options for therapeutic intervention remain limited and vary in safety and effectiveness, warranting further research to identify optimal modalities and minimize side effects. Interestingly, scalp rolling has been used as an adjuvant to topical triamcinolone acetonide.^3,5 However, the extent of its effect in combination with other therapies remains unclear. We report 3 pediatric patients with confirmed AA refractory to conventional topical treatment who experienced remarkable scalp hair regrowth after adding biweekly scalp rolling as an adjuvant therapy.

A 7-year-old boy with AA presented with 95% scalp hair loss of 7 months’ duration (Figure 1A)(patient 1). Prior treatments included mometasone solution and clobetasol solution 0.05%. After 3 months of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth after 13 months of treatment (Figure 1B). No pain, bleeding, or other side effects were reported.

An 11-year-old girl with AA presented with 100% hair loss of 7 months’ duration (Figure 2A)(patient 2). Prior treatments included fluocinonide solution and intralesional Kenalog injections. After 4 months of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth after 13 months of treatment (Figure 2B). No pain, bleeding, or other side effects were reported.

A 16-year-old boy with AA presented with 30% hair loss of 4 years’ duration (Figure 3A)(patient 3). Prior treatments included squaric acid and intralesional Kenalog injections. After 2 years of conventional topical therapy, twice-weekly scalp rolling with a 0.25-mm scalp roller of their choosing was added to the regimen, with clobetasol solution 0.05% and minoxidil foam 5% applied immediately after each scalp rolling session. The patient experienced 95% scalp hair regrowth at 17 months (Figure 3B). No pain, bleeding, or other side effects were reported.

Scalp rolling—also known as microneedling—provides a multifactorial approach to hair regrowth in patients with AA. The mechanism of action involves both the hair cycle and wound repair pathways by stimulation of the dermal papillae and stem cells.⁶ Scalp rolling has been observed to induce the expression of several hair growth pathway mediators, such as WNT3A, β-catenin, vascular endothelial growth factor, and WNT10B.⁷ Wnt/β-catenin pathway signaling is integral to multiple aspects of the hair regrowth process, including hair morphogenesis, follicle regeneration, and growth of the shaft itself.^8,9 Scalp rolling causes microinjuries to the skin, thereby diverting blood supply to the follicles and stimulating wound regeneration, a process suggested to induce follicle regeneration. This effect is due to increased expression of vascular endothelial growth factor after cutaneous injury, a mediator of both hair growth and cycling as well as wound repair.⁷ Adjuvant scalp rolling creates a synergistic effect by facilitating absorption of topical and intralesional therapies. The physical breakdown of dermal capillary barriers creates microchannels that traverse the stratum corneum, improving the permeability of small-molecule substances and allowing for relatively painless and uniform delivery of combination therapies. A secondary benefit is hypertrophy, which counteracts the atrophy caused by topical steroids via collagen induction.⁷

Additionally, scalp rolling confers minimal risk to the patient, making it safer than conventional pharmacologic therapies such as corticosteroids or Janus kinase (JAK) inhibitors. Although intralesional steroid injections are first-line treatments for limited disease, they can cause pain and skin atrophy.¹⁰ In one cohort of 54 patients, topical steroids were inferior to both oral and intralesional treatment, and oral steroids carried a systemic side-effect profile and worsening of comorbidities including hyperglycemia and hypertension as well as negative effects on bone density.¹¹ Baricitinib, a JAK inhibitor, was the first systemic treatment to gain US Food and Drug Administration approval for severe AA.¹² However, this novel therapeutic confers adverse effects including infection, acne, and hypercholesterolemia, as reported in the BRAVE-AA trials.¹³ More broadly, the US Food and Drug Administration warns of serious long-term risks such as cardiovascular events and malignancy.¹⁴ Given the tremendous potential of JAK inhibitors, further research is warranted to understand both the efficacy of topical formulations as well as the possible role of scalp rolling as its adjuvant.

Finally, scalp rolling is easily accessible and affordable to patients. Scalp rolling devices are readily available and affordable online, and they can be used autonomously at home. This pragmatic option allows patients to take control of their own treatment course and offers a financially feasible alternative to navigating insurance coverage as well as the need for extra office visits for medication refills and monitoring.

We report 3 cases of the use of scalp rolling as an adjuvant to conventional therapy for refractory AA in young patients. Although prospective research is required to establish causality and characterize age-related trends in treatment response, consideration of scalp rolling as an adjuvant to conventional therapy may help to optimize treatment regimens. Given its low risk for side effects and potential benefits, we recommend scalp rolling for patients with refractory AA.

To the Editor:

Cryptococcus neoformans is an opportunistic fungus with a predilection for immunocompromised hosts, including solid organ transplant recipients (SOTRs). However, the rapid emergence of diffuse panniculitis only upon the start of therapy for extracutaneous disease is a rare phenomenon. We report the case of a liver transplant recipient who developed a paradoxical inflammatory reaction after initiating liposomal amphotericin B therapy for disseminated C neoformans, which manifested as progressive indurated plaques histologically consistent with cryptococcal panniculitis.

A 44-year-old man who received an orthotopic liver transplant 12 months prior and was on prednisone (20 mg daily) and tacrolimus (7 mg total daily) was admitted for multifocal pneumonia complicated by septic shock. Blood and respiratory cultures grew C neoformans, and lumbar puncture evaluation of cerebrospinal fluid revealed the presence of Cryptococcus antigen in 1:40 titers. Liposomal amphotericin B 5 mg/kg intravenous daily and fluconazole 400 mg intravenous daily were administered starting on the fourth day of admission; maintenance tacrolimus and steroids were stopped. Within 36 hours of treatment initiation, an erythematous papular rash was noted on the extremities, which initially was deemed an infusion reaction. Over the next 6 days, the rash became progressively confluent and hyperpigmented. A dermatologist was consulted on the fifteenth day of admission.

Physical examination by dermatology revealed diffuse, hyperpigmented to erythematous macules on the torso, back, arms, and legs that coalesced into dusky indurated plaques along the thighs, right side of the flank, and right upper arm (Figure 1). Laboratory analysis revealed thrombocytopenia but was otherwise unremarkable. Histoplasma antigen and Coccidioides IgG and IgM enzyme immunoassays were negative, as were cytomegalovirus, HIV, and rapid plasma reagin test results. Blood culture testing was repeated, and the findings were negative.

The emergence of the rash after amphotericin initiation prompted concern that the cause was due to a drug reaction rather than cutaneous involvement of cryptococcal infection. Punch biopsies were obtained from the thigh plaque. Hematoxylin and eosin and Grocott-Gomori methenamine-silver stains revealed cryptococcal organisms in the dermis and subcutaneous fat (Figure 2). Bacterial, acid-fast bacillus, and fungal cultures showed no growth.

The patient was diagnosed with cryptococcal panniculitis. Induction therapy with liposomal amphotericin B 5 mg/kg daily and flucytosine 25 mg/kg twice daily was pursued. During the treatment, cutaneous involvement evolved into superficial desquamation. The patient ultimately died from shock secondary to persistent cryptococcal fungemia.

Cryptococcus neoformans is an opportunistic fungal infection that represents a notable hazard to SOTR, inflicting 1.5% to 2.8% of this population and carrying a 19% to 42% mortality rate.^1,2 This infection occurs at a median of 1.6 to 2.3 years after transplantation,^1,3 though liver transplant recipients and those with immune reconstitution inflammatory syndrome (IRIS)–like complications may present sooner (8.8 and 10.5 months, respectively).⁴ Cutaneous involvement comprises 17% to 21% of cases and is associated with extensive dissemination, including the central nervous system, lung, and bloodstream (61.5%, 23.1%, and 38.5%, respectively).^1-3 When Cryptococcus infects the skin, it classically manifests as multiple nodules, umbilicated papules, ulcers, or cellulitis.³ Involvement of subcutaneous adipose tissue is uncommon and primarily is observed at initial presentation alongside disseminated disease.^5-8 Our case is unique because cutaneous involvement was absent until treatment initiation.

Similar patterns of worsened or unmasked disease following treatment initiation have been observed in SOTRs with extracutaneous cryptococcus and were attributed to IRIS-like phenomena that generate a hyperactive inflammatory response to infection.^4,9 Common immunosuppressive regimens, particularly tacrolimus, depress helper T cell (T_H1) cytokine release and promote a T_H2-dominant, anti-inflammatory state.¹⁰ In cryptococcosis, the fungus itself may stimulate a comparable cytokine milieu to promote immunologic evasion and dissemination. Cryptococcal IRIS-like responses in SOTRs are precipitated by rapid reduction or withdrawal of calcineurin inhibitors and corticosteroids, in combination with the inherent mitogenicity of the C neoformans polysaccharide capsule and antifungal agents.¹⁰ In our patient, cryptococcal yeasts may have invaded subcutaneous tissues when he became fungemic but remained subclinical due to minimal inflammatory recruitment. As treatment began and immunosuppressants diminished, fungal recognition and massive cytokine release resulted in frank panniculitis via precipitous immune dysregulation.

First-line therapy of cryptococcosis entails the use of liposomal amphotericin B and flucytosine for induction, followed by fluconazole for consolidation and maintenance. Use of corticosteroids is atypical to the antifungal regimen; however, a role for them has been suggested in severe IRIS involving individuals who are HIV positive, such as those with lesions demonstrating mass effect.¹¹ Rare case reports have described their utility as adjunctive therapies against cryptococcus in SOTRs when treatment with antifungal agents alone failed.¹² Given the paucity of prospective trials to support corticosteroid use in SOTRs as well as the worse global outcomes in cases of cryptococcal meningitis,¹³ therapeutic corticosteroids were not administered in our patient.

Although our case represents a rare event, cutaneous cryptococcosis and IRIS-like phenomena are clinically relevant complications in immunocompromised patients. In particular, they should be promptly considered in SOTRs receiving maintenance immunosuppressants who demonstrate symptom aggravation despite negative microbial culture results and uninterrupted antifungal therapy.

To the Editor:

Cryptococcus neoformans is an opportunistic fungus with a predilection for immunocompromised hosts, including solid organ transplant recipients (SOTRs). However, the rapid emergence of diffuse panniculitis only upon the start of therapy for extracutaneous disease is a rare phenomenon. We report the case of a liver transplant recipient who developed a paradoxical inflammatory reaction after initiating liposomal amphotericin B therapy for disseminated C neoformans, which manifested as progressive indurated plaques histologically consistent with cryptococcal panniculitis.

A 44-year-old man who received an orthotopic liver transplant 12 months prior and was on prednisone (20 mg daily) and tacrolimus (7 mg total daily) was admitted for multifocal pneumonia complicated by septic shock. Blood and respiratory cultures grew C neoformans, and lumbar puncture evaluation of cerebrospinal fluid revealed the presence of Cryptococcus antigen in 1:40 titers. Liposomal amphotericin B 5 mg/kg intravenous daily and fluconazole 400 mg intravenous daily were administered starting on the fourth day of admission; maintenance tacrolimus and steroids were stopped. Within 36 hours of treatment initiation, an erythematous papular rash was noted on the extremities, which initially was deemed an infusion reaction. Over the next 6 days, the rash became progressively confluent and hyperpigmented. A dermatologist was consulted on the fifteenth day of admission.

Physical examination by dermatology revealed diffuse, hyperpigmented to erythematous macules on the torso, back, arms, and legs that coalesced into dusky indurated plaques along the thighs, right side of the flank, and right upper arm (Figure 1). Laboratory analysis revealed thrombocytopenia but was otherwise unremarkable. Histoplasma antigen and Coccidioides IgG and IgM enzyme immunoassays were negative, as were cytomegalovirus, HIV, and rapid plasma reagin test results. Blood culture testing was repeated, and the findings were negative.

The emergence of the rash after amphotericin initiation prompted concern that the cause was due to a drug reaction rather than cutaneous involvement of cryptococcal infection. Punch biopsies were obtained from the thigh plaque. Hematoxylin and eosin and Grocott-Gomori methenamine-silver stains revealed cryptococcal organisms in the dermis and subcutaneous fat (Figure 2). Bacterial, acid-fast bacillus, and fungal cultures showed no growth.

The patient was diagnosed with cryptococcal panniculitis. Induction therapy with liposomal amphotericin B 5 mg/kg daily and flucytosine 25 mg/kg twice daily was pursued. During the treatment, cutaneous involvement evolved into superficial desquamation. The patient ultimately died from shock secondary to persistent cryptococcal fungemia.

Cryptococcus neoformans is an opportunistic fungal infection that represents a notable hazard to SOTR, inflicting 1.5% to 2.8% of this population and carrying a 19% to 42% mortality rate.^1,2 This infection occurs at a median of 1.6 to 2.3 years after transplantation,^1,3 though liver transplant recipients and those with immune reconstitution inflammatory syndrome (IRIS)–like complications may present sooner (8.8 and 10.5 months, respectively).⁴ Cutaneous involvement comprises 17% to 21% of cases and is associated with extensive dissemination, including the central nervous system, lung, and bloodstream (61.5%, 23.1%, and 38.5%, respectively).^1-3 When Cryptococcus infects the skin, it classically manifests as multiple nodules, umbilicated papules, ulcers, or cellulitis.³ Involvement of subcutaneous adipose tissue is uncommon and primarily is observed at initial presentation alongside disseminated disease.^5-8 Our case is unique because cutaneous involvement was absent until treatment initiation.

Similar patterns of worsened or unmasked disease following treatment initiation have been observed in SOTRs with extracutaneous cryptococcus and were attributed to IRIS-like phenomena that generate a hyperactive inflammatory response to infection.^4,9 Common immunosuppressive regimens, particularly tacrolimus, depress helper T cell (T_H1) cytokine release and promote a T_H2-dominant, anti-inflammatory state.¹⁰ In cryptococcosis, the fungus itself may stimulate a comparable cytokine milieu to promote immunologic evasion and dissemination. Cryptococcal IRIS-like responses in SOTRs are precipitated by rapid reduction or withdrawal of calcineurin inhibitors and corticosteroids, in combination with the inherent mitogenicity of the C neoformans polysaccharide capsule and antifungal agents.¹⁰ In our patient, cryptococcal yeasts may have invaded subcutaneous tissues when he became fungemic but remained subclinical due to minimal inflammatory recruitment. As treatment began and immunosuppressants diminished, fungal recognition and massive cytokine release resulted in frank panniculitis via precipitous immune dysregulation.

First-line therapy of cryptococcosis entails the use of liposomal amphotericin B and flucytosine for induction, followed by fluconazole for consolidation and maintenance. Use of corticosteroids is atypical to the antifungal regimen; however, a role for them has been suggested in severe IRIS involving individuals who are HIV positive, such as those with lesions demonstrating mass effect.¹¹ Rare case reports have described their utility as adjunctive therapies against cryptococcus in SOTRs when treatment with antifungal agents alone failed.¹² Given the paucity of prospective trials to support corticosteroid use in SOTRs as well as the worse global outcomes in cases of cryptococcal meningitis,¹³ therapeutic corticosteroids were not administered in our patient.

Although our case represents a rare event, cutaneous cryptococcosis and IRIS-like phenomena are clinically relevant complications in immunocompromised patients. In particular, they should be promptly considered in SOTRs receiving maintenance immunosuppressants who demonstrate symptom aggravation despite negative microbial culture results and uninterrupted antifungal therapy.

To the Editor:

Cryptococcus neoformans is an opportunistic fungus with a predilection for immunocompromised hosts, including solid organ transplant recipients (SOTRs). However, the rapid emergence of diffuse panniculitis only upon the start of therapy for extracutaneous disease is a rare phenomenon. We report the case of a liver transplant recipient who developed a paradoxical inflammatory reaction after initiating liposomal amphotericin B therapy for disseminated C neoformans, which manifested as progressive indurated plaques histologically consistent with cryptococcal panniculitis.

A 44-year-old man who received an orthotopic liver transplant 12 months prior and was on prednisone (20 mg daily) and tacrolimus (7 mg total daily) was admitted for multifocal pneumonia complicated by septic shock. Blood and respiratory cultures grew C neoformans, and lumbar puncture evaluation of cerebrospinal fluid revealed the presence of Cryptococcus antigen in 1:40 titers. Liposomal amphotericin B 5 mg/kg intravenous daily and fluconazole 400 mg intravenous daily were administered starting on the fourth day of admission; maintenance tacrolimus and steroids were stopped. Within 36 hours of treatment initiation, an erythematous papular rash was noted on the extremities, which initially was deemed an infusion reaction. Over the next 6 days, the rash became progressively confluent and hyperpigmented. A dermatologist was consulted on the fifteenth day of admission.

Physical examination by dermatology revealed diffuse, hyperpigmented to erythematous macules on the torso, back, arms, and legs that coalesced into dusky indurated plaques along the thighs, right side of the flank, and right upper arm (Figure 1). Laboratory analysis revealed thrombocytopenia but was otherwise unremarkable. Histoplasma antigen and Coccidioides IgG and IgM enzyme immunoassays were negative, as were cytomegalovirus, HIV, and rapid plasma reagin test results. Blood culture testing was repeated, and the findings were negative.

The emergence of the rash after amphotericin initiation prompted concern that the cause was due to a drug reaction rather than cutaneous involvement of cryptococcal infection. Punch biopsies were obtained from the thigh plaque. Hematoxylin and eosin and Grocott-Gomori methenamine-silver stains revealed cryptococcal organisms in the dermis and subcutaneous fat (Figure 2). Bacterial, acid-fast bacillus, and fungal cultures showed no growth.

The patient was diagnosed with cryptococcal panniculitis. Induction therapy with liposomal amphotericin B 5 mg/kg daily and flucytosine 25 mg/kg twice daily was pursued. During the treatment, cutaneous involvement evolved into superficial desquamation. The patient ultimately died from shock secondary to persistent cryptococcal fungemia.

Cryptococcus neoformans is an opportunistic fungal infection that represents a notable hazard to SOTR, inflicting 1.5% to 2.8% of this population and carrying a 19% to 42% mortality rate.^1,2 This infection occurs at a median of 1.6 to 2.3 years after transplantation,^1,3 though liver transplant recipients and those with immune reconstitution inflammatory syndrome (IRIS)–like complications may present sooner (8.8 and 10.5 months, respectively).⁴ Cutaneous involvement comprises 17% to 21% of cases and is associated with extensive dissemination, including the central nervous system, lung, and bloodstream (61.5%, 23.1%, and 38.5%, respectively).^1-3 When Cryptococcus infects the skin, it classically manifests as multiple nodules, umbilicated papules, ulcers, or cellulitis.³ Involvement of subcutaneous adipose tissue is uncommon and primarily is observed at initial presentation alongside disseminated disease.^5-8 Our case is unique because cutaneous involvement was absent until treatment initiation.

Similar patterns of worsened or unmasked disease following treatment initiation have been observed in SOTRs with extracutaneous cryptococcus and were attributed to IRIS-like phenomena that generate a hyperactive inflammatory response to infection.^4,9 Common immunosuppressive regimens, particularly tacrolimus, depress helper T cell (T_H1) cytokine release and promote a T_H2-dominant, anti-inflammatory state.¹⁰ In cryptococcosis, the fungus itself may stimulate a comparable cytokine milieu to promote immunologic evasion and dissemination. Cryptococcal IRIS-like responses in SOTRs are precipitated by rapid reduction or withdrawal of calcineurin inhibitors and corticosteroids, in combination with the inherent mitogenicity of the C neoformans polysaccharide capsule and antifungal agents.¹⁰ In our patient, cryptococcal yeasts may have invaded subcutaneous tissues when he became fungemic but remained subclinical due to minimal inflammatory recruitment. As treatment began and immunosuppressants diminished, fungal recognition and massive cytokine release resulted in frank panniculitis via precipitous immune dysregulation.

First-line therapy of cryptococcosis entails the use of liposomal amphotericin B and flucytosine for induction, followed by fluconazole for consolidation and maintenance. Use of corticosteroids is atypical to the antifungal regimen; however, a role for them has been suggested in severe IRIS involving individuals who are HIV positive, such as those with lesions demonstrating mass effect.¹¹ Rare case reports have described their utility as adjunctive therapies against cryptococcus in SOTRs when treatment with antifungal agents alone failed.¹² Given the paucity of prospective trials to support corticosteroid use in SOTRs as well as the worse global outcomes in cases of cryptococcal meningitis,¹³ therapeutic corticosteroids were not administered in our patient.

Although our case represents a rare event, cutaneous cryptococcosis and IRIS-like phenomena are clinically relevant complications in immunocompromised patients. In particular, they should be promptly considered in SOTRs receiving maintenance immunosuppressants who demonstrate symptom aggravation despite negative microbial culture results and uninterrupted antifungal therapy.