Dermatopathology

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

The Diagnosis: Lymphomatoid Papulosis

At the time of the initial visit, a punch biopsy was performed on the posterior shoulder girdle. Histopathology revealed mild epidermal spongiosis and acanthosis with associated parakeratosis and a dermal lymphocytic infiltrate with extravasated erythrocytes consistent with pityriasis rosea (Figure 1). Two weeks after the biopsy, the patient returned for suture removal and to discuss the biopsy results. The patient reported more evolving lesions despite completing the prescribed course of dicloxacillin. At this time, physical examination revealed the persistence of several reddishbrown papules along with new nodular lesions on the arms and thighs, some with central ulceration and crusting (Figure 2). A second biopsy of a nodular lesion on the right distal forearm was performed at this visit along with a superficial tissue culture, which was negative for bacterial or fungal elements. The biopsy revealed an atypical CD30⁺ lymphoid proliferation (Figure 3). These cells were strongly PD-L1 positive and also positive for CD3, CD4, and granzyme-B. Ki67 showed a high proliferation rate, and T-cell gene rearrangement studies were positive. Given these histologic findings and the clinical context of rapidly evolving skin lesions from small papules to nodular skin tumors, a diagnosis of lymphomatoid papulosis (LyP) was established.

Because of the notable pathologic discordance between the 2 biopsy specimens, re-evaluation of the initial specimen was requested. The initial biopsy was subsequently found to be CD30⁺ with an identical peak on gene rearrangement studies as the second biopsy, further validating the diagnosis of LyP (Figure 4). Our patient was offered low-dose methotrexate therapy but declined the treatment plan, as the skin lesions had begun to resolve.

Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder with a characteristic recurrent and self-remitting disease course.^1,2 Although it typically has a benign clinical course, it is histologically malignant and considered a low-grade variant of cutaneous T-cell lymphoma. ^2,3 The classic clinical presentation of LyP involves the presence of reddish-brown papules and nodules typically measuring less than 2.0 cm, which may show evidence of central ulceration, hemorrhage, necrosis, and/or crust formation.^1-5 It is characteristic that a patient may present with these skin lesions in different stages of evolution and that biopsies of these lesions may reflect different histologic features depending on the age of the lesion, making a definitive diagnosis more difficult to obtain if not clinically correlated.^1,2 Any part of the body may be involved; however, there appears to be a predilection for the trunk and extremities in most cases.^1-3,5 The skin eruptions usually are asymptomatic, but pruritus is a commonly associated concern.^1,2,4,5

Lymphomatoid papulosis can have a localized, clustered, or generalized distribution pattern and typically will spontaneously regress without treatment within 3 to 12 weeks of symptom onset.^2,3 Lymphomatoid papulosis has a slight male predominance with a male to female ratio of 1.5:1. It occurs most commonly between 35 and 45 years of age, though it can present at any age. The overall duration of the disease can range from months to decades.^2,3 Lymphomatoid papulosis makes up approximately 15% of all cutaneous T-cell lymphomas.^2,3 Although the overall prognosis is excellent, patients with LyP are at an increased risk of developing cutaneous or systemic lymphoma, most commonly mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin lymphoma.^1-3 This increased lifelong risk is the reason that patients with LyP must be followed long-term every 6 to 12 months for surveillance of emerging malignancy.^1,2,6

The pathogenesis of LyP remains unknown. Some have hypothesized a possible viral trigger; however, there is insufficient data to support this theory.^2,6 A diagnostic hallmark of LyP is its CD30 positivity, which is a known marker for T-cell activation.6 The spontaneous regression of skin lesions that is characteristic of LyP is believed to involve the interactions between CD30 and its ligand (CD30L), which may contribute to apoptosis of neoplastic T cells.^2,3,6 With regards to the possible mechanisms contributing to tumor progression in LyP, a mutation in the transforming growth factor β receptor gene on CD30+ tumor cells within LyP lesions may allow for these cells to evade growth regulation and progress to lymphoma.^2,6 A large percentage of LyP biopsy specimens show evidence of T-cell receptor gene monoclonal rearrangement, which can aid in establishing a diagnosis.^1,2

The histologic features of LyP can vary greatly depending on the age of the lesion sampled.^1,2 Histologic subtypes of LyP have been established, with type A being the most common (approximately 75% of cases), displaying a wedge-shaped infiltrate of scattered or clustered, large, atypical CD30+ T cells.^1,2 Types B through E vary in histologic features, with the exception that all subtypes contain a CD30+ lymphocytic infiltrate.^2,3

Treatment of LyP depends on the symptom/disease burden that the patient is experiencing. For patients with a limited number of nonscarring skin lesions in areas that are not cosmetically sensitive, observation is recommended. ^1-3 For symptomatic patients with an extensive number of lesions, particularly those that may be scarring and/or in cosmetically sensitive areas, low-dose oral methotrexate therapy is considered first-line treatment.^1-4 A methotrexate dose of 5 to 20 mg weekly can be effective in reducing the number and severity of lesions, with duration of treatment depending on clinical response.^1,2 For patients who have contraindications to or who cannot tolerate oral methotrexate, phototherapy using psoralen plus UVA twice weekly for 6 to 8 weeks is another treatment option.^1,2 Topical corticosteroids also can be used in children or for patients experiencing substantial pruritus.^1,2,4 Oral or topical retinoids, topical carmustine or mechlorethamine, and brentuximab (an anti-CD30 monoclonal antibody) are all alternative therapies that have shown some beneficial effects.^1,2 In the event that any of the skin lesions do not spontaneously regress within a 3- to 12-week time frame, surgical excision or radiotherapy can be performed on those lesions.²

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is another CD30+ lymphoproliferative disorder with overlapping clinical and histopathological features of LyP. Recurrent crops of multiple lesions favor a diagnosis of LyP, whereas solitary lesions favor C-ALCL; however, multifocal C-ALCL cases may occur.² Mycosis fungoides is the most common type of cutaneous T-cell lymphoma that characteristically presents in a patch, plaque, tumor progression. Although mycosis fungoides eventually may transform into a CD30⁺ lymphoma, our patient did not display the characteristic clinical progression to suggest this diagnosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica also fall into the spectrum of clonal T-cell cutaneous disorders that more commonly affect the pediatric population. Pityriasis lichenoides et varioliformis acuta has a marked CD8⁺ lymphocyte infiltrate, whereas pityriasis lichenoides chronica has more CD4⁺ lymphocytes. These disorders typically do not stain positive for CD30.²

All patients with a diagnosis of LyP should maintain lifelong, regular, 6- to 12-month follow-up visits to monitor disease status and screen for any evidence of developing malignancy.^1,2,6 A thorough review of clinical history, complete skin examination, and physical examination with a particular focus on detection of lymphadenopathy and hepatosplenomegaly should be included at every followup visit.1 Systemic symptoms such as fever, night sweats, or weight loss are not typical features of LyP; therefore, patients who begin to develop these symptoms should be promptly evaluated for systemic lymphoma.¹

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

Background and Clinical Presentation

Seabather’s Eruption—Seabather’s eruption is a type I and IV hypersensitivity reaction caused by nematocysts of larval-stage thimble jellyfish (Linuche unguiculata), sea anemones (eg, Edwardsiella lineata), and larval cnidarians.¹Linuche unguiculata commonly is found along the southeast coast of the United States and in the Caribbean, the Gulf of Mexico, and the coasts of Florida; less commonly, it has been reported along the coasts of Brazil and Papua New Guinea. Edwardsiella lineata more commonly is seen along the East Coast of the United States.² Seabather’s eruption presents as numerous scattered, pruritic, red macules and papules (measuring 1 mm to 1.5 cm in size) distributed in areas covered by skin folds, wet clothing, or hair following exposure to marine water (Figure 1). This maculopapular rash generally appears shortly after exiting the water and can last up to several weeks in some cases.³ The cause for this delayed presentation is that the marine organisms become entrapped between the skin of the human contact and another object (eg, swimwear) but do not release their preformed antivenom until they are exposed to air after removal from the water, at which point the organisms die and cell lysis results in injection of the venom.

Diver’s Dermatitis—Diver’s dermatitis (also referred to as “swimmer’s itch”) is a type I and IV hypersensitivity reaction caused by schistosome cercariae released by aquatic snails.⁴ There are several different cercarial species known to be capable of causing diver dermatitis, but the most commonly implicated genera are Trichobilharzia and Gigantobilharzia. These parasites most commonly are found in freshwater lakes but also occur in oceans, particularly in brackish areas adjacent to freshwater access. Factors associated with increased concentrations of these parasites include shallow, slow-moving water and prolonged onshore wind causing accumulation near the shoreline. It also is thought that the snail host will shed greater concentrations of the parasitic worm in the morning hours and after prolonged exposure to sunlight.⁴ These flatworm trematodes have a 2-host life cycle. The snails function as intermediate hosts for the parasites before they enter their final host, which are birds. Humans only function as incidental and nonviable hosts for these worms. The parasites gain access to the human body by burrowing into exposed skin. Because the parasite is unable to survive on human hosts, it dies shortly after penetrating the skin, which leads to an intense inflammatory response causing symptoms of pruritus within hours of exposure (Figure 2). The initial eruption progresses over a few days into a diffuse, maculopapular, pruritic rash, similar to that seen in seabather’s eruption. This rash then regresses completely in 1 to 3 weeks. Subsequent exposure to the same parasite is associated with increased severity of future rashes, likely due to antibody-mediated sensitization.⁴

Photograph courtesy of Tomas Machacek, PhD (Prague, Czechia).

Diagnosis—Marine-derived dermatoses from various sources can present very similarly; thus, it is difficult to discern the specific etiology behind the clinical presentation. No commonly utilized imaging modalities can differentiate between seabather’s eruption and diver’s dermatitis, but eliciting a thorough patient history often can aid in differentiation of the cause of the eruption. For example, lesions located only on nonexposed areas of the skin increases the likelihood of seabather’s eruption due to nematocysts being trapped between clothing and the skin. In contrast, diver’s dermatitis generally appears on areas of the skin that were directly exposed to water and uncovered by clothing.⁵ Patient reports of a lack of symptoms until shortly after exiting the water further support a diagnosis of seabather’s eruption, as this delayed presentation of symptoms is caused by lysis of the culprit organisms following removal from the marine environment. The cell lysis is responsible for the widespread injection of preformed venom via the numerous nematocysts trapped between clothing and the patient’s body.¹

Treatment

For both conditions, the symptoms are treated with hydrocortisone or other topical steroid solutions in conjunction with oral hydroxyzine. Alternative treatments include calamine lotion with 1% menthol and nonsteroidal anti-inflammatory drugs. Taking baths with oatmeal, Epsom salts, or baking soda also may alleviate some of the pruritic symptoms.²

Prevention

The ability to diagnose the precise cause of these similar marine rashes can bring peace of mind to both patients and physicians regardless of their similar management strategies. Severe contact dermatitis of unknown etiology can be disconcerting for patients. Additionally, documenting the causes of marine rashes in particular geographic locations can be beneficial for establishing which organisms are most likely to affect visitors to those areas. This type of data collection can be utilized to develop preventative recommendations, such as deciding when to avoid the water. Education of the public can be done with the use of informational posters located near popular swimming areas and online public service announcements. Informing the general public about the dangers of entering the ocean, especially during certain times of the year when nematocyst-equipped sea creatures are in abundance, could serve to prevent numerous cases of seabather’s eruption. Likewise, advising against immersion in shallow, slow-moving water during the morning hours or after prolonged sun exposure in trematode-endemic areas could prevent numerous cases of diver’s dermatitis. Basic information on what to expect if afflicted by a marine rash also may reduce the number of emergency department visits for these conditions, thus providing economic benefit for patients and for hospitals since patients would better know how to acutely treat these rashes and lessen the patient load at hospital emergency departments. If individuals can assure themselves of the self-limited nature of these types of dermatoses, they may be less inclined to seek medical consultation.

Final Thoughts

As the climate continues to change, the incidence of marine rashes such as seabather’s eruption and diver’s dermatitis is expected to increase due to warmer surface temperatures causing more frequent and earlier blooms of L unguiculata and E lineata. Cases of diver’s dermatitis also could increase due to a longer season of more frequent human exposure from an increase in warmer temperatures. The projected uptick in incidences of these marine rashes makes understanding these pathologies even more pertinent for physicians.⁶ Increasing our understanding of the different types of marine rashes and their causes will help guide future recommendations for the general public when visiting the ocean.

Future research may wish to investigate unique ways in which to prevent contact between these organisms and humans. Past research on mice indicated that topical application of DEET (N,N-diethyl-meta-toluamide) prior to trematode exposure prevented penetration of the skin by parasitic worms.⁷ Future studies are needed to examine the effectiveness of this preventative technique on humans. For now, dermatologists may counsel our ocean-going patients on preventative behaviors as well as provide reassurance and symptomatic relief when they present to our clinics with marine rashes.

Background and Clinical Presentation

Seabather’s Eruption—Seabather’s eruption is a type I and IV hypersensitivity reaction caused by nematocysts of larval-stage thimble jellyfish (Linuche unguiculata), sea anemones (eg, Edwardsiella lineata), and larval cnidarians.¹Linuche unguiculata commonly is found along the southeast coast of the United States and in the Caribbean, the Gulf of Mexico, and the coasts of Florida; less commonly, it has been reported along the coasts of Brazil and Papua New Guinea. Edwardsiella lineata more commonly is seen along the East Coast of the United States.² Seabather’s eruption presents as numerous scattered, pruritic, red macules and papules (measuring 1 mm to 1.5 cm in size) distributed in areas covered by skin folds, wet clothing, or hair following exposure to marine water (Figure 1). This maculopapular rash generally appears shortly after exiting the water and can last up to several weeks in some cases.³ The cause for this delayed presentation is that the marine organisms become entrapped between the skin of the human contact and another object (eg, swimwear) but do not release their preformed antivenom until they are exposed to air after removal from the water, at which point the organisms die and cell lysis results in injection of the venom.

Diver’s Dermatitis—Diver’s dermatitis (also referred to as “swimmer’s itch”) is a type I and IV hypersensitivity reaction caused by schistosome cercariae released by aquatic snails.⁴ There are several different cercarial species known to be capable of causing diver dermatitis, but the most commonly implicated genera are Trichobilharzia and Gigantobilharzia. These parasites most commonly are found in freshwater lakes but also occur in oceans, particularly in brackish areas adjacent to freshwater access. Factors associated with increased concentrations of these parasites include shallow, slow-moving water and prolonged onshore wind causing accumulation near the shoreline. It also is thought that the snail host will shed greater concentrations of the parasitic worm in the morning hours and after prolonged exposure to sunlight.⁴ These flatworm trematodes have a 2-host life cycle. The snails function as intermediate hosts for the parasites before they enter their final host, which are birds. Humans only function as incidental and nonviable hosts for these worms. The parasites gain access to the human body by burrowing into exposed skin. Because the parasite is unable to survive on human hosts, it dies shortly after penetrating the skin, which leads to an intense inflammatory response causing symptoms of pruritus within hours of exposure (Figure 2). The initial eruption progresses over a few days into a diffuse, maculopapular, pruritic rash, similar to that seen in seabather’s eruption. This rash then regresses completely in 1 to 3 weeks. Subsequent exposure to the same parasite is associated with increased severity of future rashes, likely due to antibody-mediated sensitization.⁴

Photograph courtesy of Tomas Machacek, PhD (Prague, Czechia).

Diagnosis—Marine-derived dermatoses from various sources can present very similarly; thus, it is difficult to discern the specific etiology behind the clinical presentation. No commonly utilized imaging modalities can differentiate between seabather’s eruption and diver’s dermatitis, but eliciting a thorough patient history often can aid in differentiation of the cause of the eruption. For example, lesions located only on nonexposed areas of the skin increases the likelihood of seabather’s eruption due to nematocysts being trapped between clothing and the skin. In contrast, diver’s dermatitis generally appears on areas of the skin that were directly exposed to water and uncovered by clothing.⁵ Patient reports of a lack of symptoms until shortly after exiting the water further support a diagnosis of seabather’s eruption, as this delayed presentation of symptoms is caused by lysis of the culprit organisms following removal from the marine environment. The cell lysis is responsible for the widespread injection of preformed venom via the numerous nematocysts trapped between clothing and the patient’s body.¹

Treatment

For both conditions, the symptoms are treated with hydrocortisone or other topical steroid solutions in conjunction with oral hydroxyzine. Alternative treatments include calamine lotion with 1% menthol and nonsteroidal anti-inflammatory drugs. Taking baths with oatmeal, Epsom salts, or baking soda also may alleviate some of the pruritic symptoms.²

Prevention

The ability to diagnose the precise cause of these similar marine rashes can bring peace of mind to both patients and physicians regardless of their similar management strategies. Severe contact dermatitis of unknown etiology can be disconcerting for patients. Additionally, documenting the causes of marine rashes in particular geographic locations can be beneficial for establishing which organisms are most likely to affect visitors to those areas. This type of data collection can be utilized to develop preventative recommendations, such as deciding when to avoid the water. Education of the public can be done with the use of informational posters located near popular swimming areas and online public service announcements. Informing the general public about the dangers of entering the ocean, especially during certain times of the year when nematocyst-equipped sea creatures are in abundance, could serve to prevent numerous cases of seabather’s eruption. Likewise, advising against immersion in shallow, slow-moving water during the morning hours or after prolonged sun exposure in trematode-endemic areas could prevent numerous cases of diver’s dermatitis. Basic information on what to expect if afflicted by a marine rash also may reduce the number of emergency department visits for these conditions, thus providing economic benefit for patients and for hospitals since patients would better know how to acutely treat these rashes and lessen the patient load at hospital emergency departments. If individuals can assure themselves of the self-limited nature of these types of dermatoses, they may be less inclined to seek medical consultation.

Final Thoughts

As the climate continues to change, the incidence of marine rashes such as seabather’s eruption and diver’s dermatitis is expected to increase due to warmer surface temperatures causing more frequent and earlier blooms of L unguiculata and E lineata. Cases of diver’s dermatitis also could increase due to a longer season of more frequent human exposure from an increase in warmer temperatures. The projected uptick in incidences of these marine rashes makes understanding these pathologies even more pertinent for physicians.⁶ Increasing our understanding of the different types of marine rashes and their causes will help guide future recommendations for the general public when visiting the ocean.

Future research may wish to investigate unique ways in which to prevent contact between these organisms and humans. Past research on mice indicated that topical application of DEET (N,N-diethyl-meta-toluamide) prior to trematode exposure prevented penetration of the skin by parasitic worms.⁷ Future studies are needed to examine the effectiveness of this preventative technique on humans. For now, dermatologists may counsel our ocean-going patients on preventative behaviors as well as provide reassurance and symptomatic relief when they present to our clinics with marine rashes.

Background and Clinical Presentation

Seabather’s Eruption—Seabather’s eruption is a type I and IV hypersensitivity reaction caused by nematocysts of larval-stage thimble jellyfish (Linuche unguiculata), sea anemones (eg, Edwardsiella lineata), and larval cnidarians.¹Linuche unguiculata commonly is found along the southeast coast of the United States and in the Caribbean, the Gulf of Mexico, and the coasts of Florida; less commonly, it has been reported along the coasts of Brazil and Papua New Guinea. Edwardsiella lineata more commonly is seen along the East Coast of the United States.² Seabather’s eruption presents as numerous scattered, pruritic, red macules and papules (measuring 1 mm to 1.5 cm in size) distributed in areas covered by skin folds, wet clothing, or hair following exposure to marine water (Figure 1). This maculopapular rash generally appears shortly after exiting the water and can last up to several weeks in some cases.³ The cause for this delayed presentation is that the marine organisms become entrapped between the skin of the human contact and another object (eg, swimwear) but do not release their preformed antivenom until they are exposed to air after removal from the water, at which point the organisms die and cell lysis results in injection of the venom.

Diver’s Dermatitis—Diver’s dermatitis (also referred to as “swimmer’s itch”) is a type I and IV hypersensitivity reaction caused by schistosome cercariae released by aquatic snails.⁴ There are several different cercarial species known to be capable of causing diver dermatitis, but the most commonly implicated genera are Trichobilharzia and Gigantobilharzia. These parasites most commonly are found in freshwater lakes but also occur in oceans, particularly in brackish areas adjacent to freshwater access. Factors associated with increased concentrations of these parasites include shallow, slow-moving water and prolonged onshore wind causing accumulation near the shoreline. It also is thought that the snail host will shed greater concentrations of the parasitic worm in the morning hours and after prolonged exposure to sunlight.⁴ These flatworm trematodes have a 2-host life cycle. The snails function as intermediate hosts for the parasites before they enter their final host, which are birds. Humans only function as incidental and nonviable hosts for these worms. The parasites gain access to the human body by burrowing into exposed skin. Because the parasite is unable to survive on human hosts, it dies shortly after penetrating the skin, which leads to an intense inflammatory response causing symptoms of pruritus within hours of exposure (Figure 2). The initial eruption progresses over a few days into a diffuse, maculopapular, pruritic rash, similar to that seen in seabather’s eruption. This rash then regresses completely in 1 to 3 weeks. Subsequent exposure to the same parasite is associated with increased severity of future rashes, likely due to antibody-mediated sensitization.⁴

Photograph courtesy of Tomas Machacek, PhD (Prague, Czechia).

Diagnosis—Marine-derived dermatoses from various sources can present very similarly; thus, it is difficult to discern the specific etiology behind the clinical presentation. No commonly utilized imaging modalities can differentiate between seabather’s eruption and diver’s dermatitis, but eliciting a thorough patient history often can aid in differentiation of the cause of the eruption. For example, lesions located only on nonexposed areas of the skin increases the likelihood of seabather’s eruption due to nematocysts being trapped between clothing and the skin. In contrast, diver’s dermatitis generally appears on areas of the skin that were directly exposed to water and uncovered by clothing.⁵ Patient reports of a lack of symptoms until shortly after exiting the water further support a diagnosis of seabather’s eruption, as this delayed presentation of symptoms is caused by lysis of the culprit organisms following removal from the marine environment. The cell lysis is responsible for the widespread injection of preformed venom via the numerous nematocysts trapped between clothing and the patient’s body.¹

Treatment

For both conditions, the symptoms are treated with hydrocortisone or other topical steroid solutions in conjunction with oral hydroxyzine. Alternative treatments include calamine lotion with 1% menthol and nonsteroidal anti-inflammatory drugs. Taking baths with oatmeal, Epsom salts, or baking soda also may alleviate some of the pruritic symptoms.²

Prevention

The ability to diagnose the precise cause of these similar marine rashes can bring peace of mind to both patients and physicians regardless of their similar management strategies. Severe contact dermatitis of unknown etiology can be disconcerting for patients. Additionally, documenting the causes of marine rashes in particular geographic locations can be beneficial for establishing which organisms are most likely to affect visitors to those areas. This type of data collection can be utilized to develop preventative recommendations, such as deciding when to avoid the water. Education of the public can be done with the use of informational posters located near popular swimming areas and online public service announcements. Informing the general public about the dangers of entering the ocean, especially during certain times of the year when nematocyst-equipped sea creatures are in abundance, could serve to prevent numerous cases of seabather’s eruption. Likewise, advising against immersion in shallow, slow-moving water during the morning hours or after prolonged sun exposure in trematode-endemic areas could prevent numerous cases of diver’s dermatitis. Basic information on what to expect if afflicted by a marine rash also may reduce the number of emergency department visits for these conditions, thus providing economic benefit for patients and for hospitals since patients would better know how to acutely treat these rashes and lessen the patient load at hospital emergency departments. If individuals can assure themselves of the self-limited nature of these types of dermatoses, they may be less inclined to seek medical consultation.

Final Thoughts

As the climate continues to change, the incidence of marine rashes such as seabather’s eruption and diver’s dermatitis is expected to increase due to warmer surface temperatures causing more frequent and earlier blooms of L unguiculata and E lineata. Cases of diver’s dermatitis also could increase due to a longer season of more frequent human exposure from an increase in warmer temperatures. The projected uptick in incidences of these marine rashes makes understanding these pathologies even more pertinent for physicians.⁶ Increasing our understanding of the different types of marine rashes and their causes will help guide future recommendations for the general public when visiting the ocean.

Future research may wish to investigate unique ways in which to prevent contact between these organisms and humans. Past research on mice indicated that topical application of DEET (N,N-diethyl-meta-toluamide) prior to trematode exposure prevented penetration of the skin by parasitic worms.⁷ Future studies are needed to examine the effectiveness of this preventative technique on humans. For now, dermatologists may counsel our ocean-going patients on preventative behaviors as well as provide reassurance and symptomatic relief when they present to our clinics with marine rashes.

The Diagnosis: Metastatic Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a common genitourinary system malignancy with incidence peaking between 50 and 70 years of age and a male predominance.¹ The clear cell variant is the most common subtype of RCC, accounting for 70% to 75% of all cases. It is known to be a highly aggressive malignancy that frequently metastasizes to the lungs, lymphatics, bones, liver, and brain.^2,3 Approximately 20% to 50% of patients with RCC eventually will develop metastasis after nephrectomy.⁴ Survival with metastatic RCC to any site typically is in the range of 10 to 22 months.^5,6 Cutaneous metastases of RCC rarely have been reported in the literature (3%–6% of cases⁷) and most commonly are found on the scalp, followed by the chest or abdomen. ⁸ Cutaneous metastases generally are regarded as a late manifestation of the disease with a very poor prognosis. ⁹ It is unusual to identify cutaneous RCC metastasis without known RCC or other symptoms consistent with advanced RCC, such as hematuria or abdominal/flank pain. Renal cell carcinoma accounts for an estimated 6% to 7% of all cutaneous metastatic lesions.¹⁰ Cutaneous metastatic lesions of RCC often are solitary and grow rapidly, with the clinical appearance of an erythematous or violaceous, nodular, highly vascular, and often hemorrhagic growth.^9,11,12

Following the histologic diagnosis of metastatic clear cell RCC, our patient was referred to medical oncology for further workup. Magnetic resonance imaging and a positron emission tomography scan demonstrated widespread disease with a 7-cm left renal mass, liver and lung metastases, and bilateral mediastinal lymphadenopathy. The patient was started on combination immunotherapy as a palliative treatment given the widespread disease.

Histologically, clear cell RCC is characterized by lipid and glycogen-rich cells with ample cytoplasm and a well-developed vascular network, which often is thin walled with a chicken wire–like architecture. Metastatic clear cell RCC tumor cells may form glandular, acinar, or papillary structures with variable lymphocytic inflammatory infiltrates and abundant capillary formation. Immunohistochemically, the tumor cells should demonstrate positivity for paired box gene 8, PAX8, and RCC marker antigen.¹³ Vimentin and carcinoembryonic antigen may be utilized to distinguish from hidradenoma as carcinoembryonic antigen will be positive in hidradenoma and vimentin will be negative.¹⁴ Renal cell carcinoma also has a common molecular signature of von Hippel-Lindau tumor suppressor gene inactivation as well as upregulation of hypoxia inducible factor and vascular endothelial growth factor.¹⁵

Balloon cell nevi often clinically present in young patients as bicolored nevi that sometimes are polypoid or verrucous in appearance with central yellow globules surrounded by a peripheral reticular pattern on dermoscopy. Histologically, balloon cell nevi are characterized by large cells with small, round, centrally located basophilic nuclei and clear foamy cytoplasm (Figure 1), which are thought to be formed by progressive vacuolization of melanocytes due to the enlargement and disintegration of melanosomes. This ballooning change reflects an seen in malignant melanoma, in which case nuclear pleomorphism, atypia, and increased mitotic activity also are observed. The prominent vascular network characteristic of RCC typically is not present.¹⁶

Clear cell hidradenomas are benign skin appendage tumors that often present as small, firm, solitary dermal nodules that may extend into the subcutaneous fat. They have a predilection for the head, face, and arms and demonstrate 2 predominant cell types, including a polyhedral cell with a rounded nucleus and slightly basophilic cytoplasm as well as a round cell with clear cytoplasm and bland nuclei (Figure 2). The latter cell type is less common, representing the predominant cell type in less than one-third of hidradenomas, and can present a diagnostic quandary based on histologic similarity to other clear cell neoplasms. The clear cells contain glycogen but no lipid. Ductlike structures often are present, and the intervening stroma varies from delicate vascularized cords of fibrous tissue to dense hyalinized collagen. Immunohistochemistry may be required for definitive diagnosis, and clear cell hidradenomas should react with monoclonal antibodies that label both eccrine and apocrine secretory elements, such as cytokeratins 6/18, 7, and 8/18.¹⁷

Pyogenic granulomas (also referred to as lobular capillary hemangiomas) are common and present clinically as rapidly growing, polypoid, red masses surrounded by a thickened epidermis that often are found on the fingers or lips. This entity is benign and often regresses spontaneously. Histologically, pyogenic granulomas are characterized by a lobular pattern of vascular proliferation associated with edema and inflammation resembling granulation tissue, with acanthosis and hyperkeratosis at the edges of the lesion (Figure 3).¹⁸

Sebaceous carcinoma is a locally aggressive malignant neoplasm arising from the cells of the sebaceous glands and occurring most commonly in the periorbital area. This neoplasm most often affects older adults, with a mean age at diagnosis of 63 to 77 years. It commonly presents as a solitary nodule with yellowish discoloration and madarosis, which is a key distinguishing feature to differentiate this entity from a chalazion or hordeolum. Histologically, sebaceous carcinoma is a dermal-based infiltrative, nodular tumor with varying degrees of clear cell changes—well-differentiated tumors show more clear cell change as compared to more poorly differentiated variants—along with basaloid or squamous features and abundant mitotic activity (Figure 4), which may be useful in distinguishing it from the other entities in the clear cell neoplasm differential.^19-22

The Diagnosis: Metastatic Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a common genitourinary system malignancy with incidence peaking between 50 and 70 years of age and a male predominance.¹ The clear cell variant is the most common subtype of RCC, accounting for 70% to 75% of all cases. It is known to be a highly aggressive malignancy that frequently metastasizes to the lungs, lymphatics, bones, liver, and brain.^2,3 Approximately 20% to 50% of patients with RCC eventually will develop metastasis after nephrectomy.⁴ Survival with metastatic RCC to any site typically is in the range of 10 to 22 months.^5,6 Cutaneous metastases of RCC rarely have been reported in the literature (3%–6% of cases⁷) and most commonly are found on the scalp, followed by the chest or abdomen. ⁸ Cutaneous metastases generally are regarded as a late manifestation of the disease with a very poor prognosis. ⁹ It is unusual to identify cutaneous RCC metastasis without known RCC or other symptoms consistent with advanced RCC, such as hematuria or abdominal/flank pain. Renal cell carcinoma accounts for an estimated 6% to 7% of all cutaneous metastatic lesions.¹⁰ Cutaneous metastatic lesions of RCC often are solitary and grow rapidly, with the clinical appearance of an erythematous or violaceous, nodular, highly vascular, and often hemorrhagic growth.^9,11,12

Following the histologic diagnosis of metastatic clear cell RCC, our patient was referred to medical oncology for further workup. Magnetic resonance imaging and a positron emission tomography scan demonstrated widespread disease with a 7-cm left renal mass, liver and lung metastases, and bilateral mediastinal lymphadenopathy. The patient was started on combination immunotherapy as a palliative treatment given the widespread disease.

Histologically, clear cell RCC is characterized by lipid and glycogen-rich cells with ample cytoplasm and a well-developed vascular network, which often is thin walled with a chicken wire–like architecture. Metastatic clear cell RCC tumor cells may form glandular, acinar, or papillary structures with variable lymphocytic inflammatory infiltrates and abundant capillary formation. Immunohistochemically, the tumor cells should demonstrate positivity for paired box gene 8, PAX8, and RCC marker antigen.¹³ Vimentin and carcinoembryonic antigen may be utilized to distinguish from hidradenoma as carcinoembryonic antigen will be positive in hidradenoma and vimentin will be negative.¹⁴ Renal cell carcinoma also has a common molecular signature of von Hippel-Lindau tumor suppressor gene inactivation as well as upregulation of hypoxia inducible factor and vascular endothelial growth factor.¹⁵

Balloon cell nevi often clinically present in young patients as bicolored nevi that sometimes are polypoid or verrucous in appearance with central yellow globules surrounded by a peripheral reticular pattern on dermoscopy. Histologically, balloon cell nevi are characterized by large cells with small, round, centrally located basophilic nuclei and clear foamy cytoplasm (Figure 1), which are thought to be formed by progressive vacuolization of melanocytes due to the enlargement and disintegration of melanosomes. This ballooning change reflects an seen in malignant melanoma, in which case nuclear pleomorphism, atypia, and increased mitotic activity also are observed. The prominent vascular network characteristic of RCC typically is not present.¹⁶

Clear cell hidradenomas are benign skin appendage tumors that often present as small, firm, solitary dermal nodules that may extend into the subcutaneous fat. They have a predilection for the head, face, and arms and demonstrate 2 predominant cell types, including a polyhedral cell with a rounded nucleus and slightly basophilic cytoplasm as well as a round cell with clear cytoplasm and bland nuclei (Figure 2). The latter cell type is less common, representing the predominant cell type in less than one-third of hidradenomas, and can present a diagnostic quandary based on histologic similarity to other clear cell neoplasms. The clear cells contain glycogen but no lipid. Ductlike structures often are present, and the intervening stroma varies from delicate vascularized cords of fibrous tissue to dense hyalinized collagen. Immunohistochemistry may be required for definitive diagnosis, and clear cell hidradenomas should react with monoclonal antibodies that label both eccrine and apocrine secretory elements, such as cytokeratins 6/18, 7, and 8/18.¹⁷

Pyogenic granulomas (also referred to as lobular capillary hemangiomas) are common and present clinically as rapidly growing, polypoid, red masses surrounded by a thickened epidermis that often are found on the fingers or lips. This entity is benign and often regresses spontaneously. Histologically, pyogenic granulomas are characterized by a lobular pattern of vascular proliferation associated with edema and inflammation resembling granulation tissue, with acanthosis and hyperkeratosis at the edges of the lesion (Figure 3).¹⁸

Sebaceous carcinoma is a locally aggressive malignant neoplasm arising from the cells of the sebaceous glands and occurring most commonly in the periorbital area. This neoplasm most often affects older adults, with a mean age at diagnosis of 63 to 77 years. It commonly presents as a solitary nodule with yellowish discoloration and madarosis, which is a key distinguishing feature to differentiate this entity from a chalazion or hordeolum. Histologically, sebaceous carcinoma is a dermal-based infiltrative, nodular tumor with varying degrees of clear cell changes—well-differentiated tumors show more clear cell change as compared to more poorly differentiated variants—along with basaloid or squamous features and abundant mitotic activity (Figure 4), which may be useful in distinguishing it from the other entities in the clear cell neoplasm differential.^19-22

The Diagnosis: Metastatic Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a common genitourinary system malignancy with incidence peaking between 50 and 70 years of age and a male predominance.¹ The clear cell variant is the most common subtype of RCC, accounting for 70% to 75% of all cases. It is known to be a highly aggressive malignancy that frequently metastasizes to the lungs, lymphatics, bones, liver, and brain.^2,3 Approximately 20% to 50% of patients with RCC eventually will develop metastasis after nephrectomy.⁴ Survival with metastatic RCC to any site typically is in the range of 10 to 22 months.^5,6 Cutaneous metastases of RCC rarely have been reported in the literature (3%–6% of cases⁷) and most commonly are found on the scalp, followed by the chest or abdomen. ⁸ Cutaneous metastases generally are regarded as a late manifestation of the disease with a very poor prognosis. ⁹ It is unusual to identify cutaneous RCC metastasis without known RCC or other symptoms consistent with advanced RCC, such as hematuria or abdominal/flank pain. Renal cell carcinoma accounts for an estimated 6% to 7% of all cutaneous metastatic lesions.¹⁰ Cutaneous metastatic lesions of RCC often are solitary and grow rapidly, with the clinical appearance of an erythematous or violaceous, nodular, highly vascular, and often hemorrhagic growth.^9,11,12

Following the histologic diagnosis of metastatic clear cell RCC, our patient was referred to medical oncology for further workup. Magnetic resonance imaging and a positron emission tomography scan demonstrated widespread disease with a 7-cm left renal mass, liver and lung metastases, and bilateral mediastinal lymphadenopathy. The patient was started on combination immunotherapy as a palliative treatment given the widespread disease.

Histologically, clear cell RCC is characterized by lipid and glycogen-rich cells with ample cytoplasm and a well-developed vascular network, which often is thin walled with a chicken wire–like architecture. Metastatic clear cell RCC tumor cells may form glandular, acinar, or papillary structures with variable lymphocytic inflammatory infiltrates and abundant capillary formation. Immunohistochemically, the tumor cells should demonstrate positivity for paired box gene 8, PAX8, and RCC marker antigen.¹³ Vimentin and carcinoembryonic antigen may be utilized to distinguish from hidradenoma as carcinoembryonic antigen will be positive in hidradenoma and vimentin will be negative.¹⁴ Renal cell carcinoma also has a common molecular signature of von Hippel-Lindau tumor suppressor gene inactivation as well as upregulation of hypoxia inducible factor and vascular endothelial growth factor.¹⁵

Balloon cell nevi often clinically present in young patients as bicolored nevi that sometimes are polypoid or verrucous in appearance with central yellow globules surrounded by a peripheral reticular pattern on dermoscopy. Histologically, balloon cell nevi are characterized by large cells with small, round, centrally located basophilic nuclei and clear foamy cytoplasm (Figure 1), which are thought to be formed by progressive vacuolization of melanocytes due to the enlargement and disintegration of melanosomes. This ballooning change reflects an seen in malignant melanoma, in which case nuclear pleomorphism, atypia, and increased mitotic activity also are observed. The prominent vascular network characteristic of RCC typically is not present.¹⁶

Clear cell hidradenomas are benign skin appendage tumors that often present as small, firm, solitary dermal nodules that may extend into the subcutaneous fat. They have a predilection for the head, face, and arms and demonstrate 2 predominant cell types, including a polyhedral cell with a rounded nucleus and slightly basophilic cytoplasm as well as a round cell with clear cytoplasm and bland nuclei (Figure 2). The latter cell type is less common, representing the predominant cell type in less than one-third of hidradenomas, and can present a diagnostic quandary based on histologic similarity to other clear cell neoplasms. The clear cells contain glycogen but no lipid. Ductlike structures often are present, and the intervening stroma varies from delicate vascularized cords of fibrous tissue to dense hyalinized collagen. Immunohistochemistry may be required for definitive diagnosis, and clear cell hidradenomas should react with monoclonal antibodies that label both eccrine and apocrine secretory elements, such as cytokeratins 6/18, 7, and 8/18.¹⁷

Pyogenic granulomas (also referred to as lobular capillary hemangiomas) are common and present clinically as rapidly growing, polypoid, red masses surrounded by a thickened epidermis that often are found on the fingers or lips. This entity is benign and often regresses spontaneously. Histologically, pyogenic granulomas are characterized by a lobular pattern of vascular proliferation associated with edema and inflammation resembling granulation tissue, with acanthosis and hyperkeratosis at the edges of the lesion (Figure 3).¹⁸

Sebaceous carcinoma is a locally aggressive malignant neoplasm arising from the cells of the sebaceous glands and occurring most commonly in the periorbital area. This neoplasm most often affects older adults, with a mean age at diagnosis of 63 to 77 years. It commonly presents as a solitary nodule with yellowish discoloration and madarosis, which is a key distinguishing feature to differentiate this entity from a chalazion or hordeolum. Histologically, sebaceous carcinoma is a dermal-based infiltrative, nodular tumor with varying degrees of clear cell changes—well-differentiated tumors show more clear cell change as compared to more poorly differentiated variants—along with basaloid or squamous features and abundant mitotic activity (Figure 4), which may be useful in distinguishing it from the other entities in the clear cell neoplasm differential.^19-22