Richard J. Antaya, MD

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

The Diagnosis: Langerhans Cell Histiocytosis 

Langerhans cell histiocytosis (LCH) is a clonal proliferative disorder of Langerhans cells that can affect any organ, most commonly the skin and bones. It typically develops in children aged 1 to 3 years, with a male to female ratio of 2 to 1.¹ Skin manifestations include purpuric papules, pustules, vesicles, erosions, and fissuring distributed predominantly on the scalp and flexural sites. Mucosal sites, particularly the oral mucosa, may be involved and usually present as erosions associated with underlying bone lesions.¹ Langerhans cell histiocytosis should be considered in the differential diagnosis of recalcitrant diaper dermatitis in an infant, especially when there is purpura and erosions, as seen in our patient. Common conditions in infants such as cutaneous candidiasis (intense erythema with superficial erosions, peripheral scale and satellite pustules on flexural areas, potassium hydroxide microscopy revealing yeast forms and pseudohyphae) and seborrheic dermatitis (well-defined pink to red, moist, and often scaly patches favoring the folds) may be distinguished clinically from Hailey-Hailey disease (malodorous plaques with fissures and erosions favoring the folds), which is rare in infancy, and acrodermatitis enteropathica (erythema and erosions with scale-crust and desquamation on periorificial, acral, and intertriginous skin).

Histopathologic evaluation is instrumental in diagnosing the skin lesions of LCH. Further evaluation for systemic involvement is necessary once the diagnosis is made. Skin biopsy of the scalp and right inguinal fold revealed a wedge-shaped infiltrate of histiocytes with slightly folded nuclear contours in our patient (Figure 1). CD1a (Figure 2) and S-100 stains were markedly positive, which is characteristic of LCH. Complete blood cell count, renal function, liver function, urinalysis, and flow cytometry results were within reference range. A skeletal survey and echocardiogram were unremarkable; however, mild hepatosplenomegaly was noted on abdominal ultrasonography.

Treatment of LCH varies based on the extent of organ involvement. For isolated cutaneous disease, topical steroids, topical nitrogen mustard, phototherapy, and thalidomide may be employed.² Multisystem disease requires chemotherapeutic agents including vinblastine and prednisone.^2,3 Because more than half of patients with LCH have oncogenic BRAF V600E mutations,⁴ vemurafenib may have a therapeutic role in treatment. Rare case reports have documented disease response in patients with LCH and Erdheim-Chester disease.^5,6 

Prognosis varies based on age and extent of systemic involvement. Children younger than 2 years with multiorgan involvement have a poor prognosis (35%-55% mortality rate) compared to older children without hematopoietic, hepatosplenic, or lung involvement (100% survival rate). Additionally, response to treatment affects prognosis, as there is a 66% mortality rate in those who do not respond to treatment after 6 weeks.³ Long-term sequelae of LCH include endocrine dysfunction (ie, diabetes insipidus, growth hormone deficiencies), hearing impairment, orthopedic impairment, and neuropsychological disease; thus, multidisciplinary care often is neccessary.⁷

Given the multisystem involvement in our patient, he was treated with vinblastine, 6-mercaptopurine, and prednisolone with only partial and transient disease response. He was then treated with clofarabine with dramatic resolution of the mediastinal mass on follow-up positron emission tomography. The cutaneous lesions persisted and were managed with topical corticosteroids.

The Diagnosis: Langerhans Cell Histiocytosis 

Langerhans cell histiocytosis (LCH) is a clonal proliferative disorder of Langerhans cells that can affect any organ, most commonly the skin and bones. It typically develops in children aged 1 to 3 years, with a male to female ratio of 2 to 1.¹ Skin manifestations include purpuric papules, pustules, vesicles, erosions, and fissuring distributed predominantly on the scalp and flexural sites. Mucosal sites, particularly the oral mucosa, may be involved and usually present as erosions associated with underlying bone lesions.¹ Langerhans cell histiocytosis should be considered in the differential diagnosis of recalcitrant diaper dermatitis in an infant, especially when there is purpura and erosions, as seen in our patient. Common conditions in infants such as cutaneous candidiasis (intense erythema with superficial erosions, peripheral scale and satellite pustules on flexural areas, potassium hydroxide microscopy revealing yeast forms and pseudohyphae) and seborrheic dermatitis (well-defined pink to red, moist, and often scaly patches favoring the folds) may be distinguished clinically from Hailey-Hailey disease (malodorous plaques with fissures and erosions favoring the folds), which is rare in infancy, and acrodermatitis enteropathica (erythema and erosions with scale-crust and desquamation on periorificial, acral, and intertriginous skin).

Histopathologic evaluation is instrumental in diagnosing the skin lesions of LCH. Further evaluation for systemic involvement is necessary once the diagnosis is made. Skin biopsy of the scalp and right inguinal fold revealed a wedge-shaped infiltrate of histiocytes with slightly folded nuclear contours in our patient (Figure 1). CD1a (Figure 2) and S-100 stains were markedly positive, which is characteristic of LCH. Complete blood cell count, renal function, liver function, urinalysis, and flow cytometry results were within reference range. A skeletal survey and echocardiogram were unremarkable; however, mild hepatosplenomegaly was noted on abdominal ultrasonography.

Treatment of LCH varies based on the extent of organ involvement. For isolated cutaneous disease, topical steroids, topical nitrogen mustard, phototherapy, and thalidomide may be employed.² Multisystem disease requires chemotherapeutic agents including vinblastine and prednisone.^2,3 Because more than half of patients with LCH have oncogenic BRAF V600E mutations,⁴ vemurafenib may have a therapeutic role in treatment. Rare case reports have documented disease response in patients with LCH and Erdheim-Chester disease.^5,6 

Prognosis varies based on age and extent of systemic involvement. Children younger than 2 years with multiorgan involvement have a poor prognosis (35%-55% mortality rate) compared to older children without hematopoietic, hepatosplenic, or lung involvement (100% survival rate). Additionally, response to treatment affects prognosis, as there is a 66% mortality rate in those who do not respond to treatment after 6 weeks.³ Long-term sequelae of LCH include endocrine dysfunction (ie, diabetes insipidus, growth hormone deficiencies), hearing impairment, orthopedic impairment, and neuropsychological disease; thus, multidisciplinary care often is neccessary.⁷

Given the multisystem involvement in our patient, he was treated with vinblastine, 6-mercaptopurine, and prednisolone with only partial and transient disease response. He was then treated with clofarabine with dramatic resolution of the mediastinal mass on follow-up positron emission tomography. The cutaneous lesions persisted and were managed with topical corticosteroids.

The Diagnosis: Langerhans Cell Histiocytosis 

Langerhans cell histiocytosis (LCH) is a clonal proliferative disorder of Langerhans cells that can affect any organ, most commonly the skin and bones. It typically develops in children aged 1 to 3 years, with a male to female ratio of 2 to 1.¹ Skin manifestations include purpuric papules, pustules, vesicles, erosions, and fissuring distributed predominantly on the scalp and flexural sites. Mucosal sites, particularly the oral mucosa, may be involved and usually present as erosions associated with underlying bone lesions.¹ Langerhans cell histiocytosis should be considered in the differential diagnosis of recalcitrant diaper dermatitis in an infant, especially when there is purpura and erosions, as seen in our patient. Common conditions in infants such as cutaneous candidiasis (intense erythema with superficial erosions, peripheral scale and satellite pustules on flexural areas, potassium hydroxide microscopy revealing yeast forms and pseudohyphae) and seborrheic dermatitis (well-defined pink to red, moist, and often scaly patches favoring the folds) may be distinguished clinically from Hailey-Hailey disease (malodorous plaques with fissures and erosions favoring the folds), which is rare in infancy, and acrodermatitis enteropathica (erythema and erosions with scale-crust and desquamation on periorificial, acral, and intertriginous skin).

Histopathologic evaluation is instrumental in diagnosing the skin lesions of LCH. Further evaluation for systemic involvement is necessary once the diagnosis is made. Skin biopsy of the scalp and right inguinal fold revealed a wedge-shaped infiltrate of histiocytes with slightly folded nuclear contours in our patient (Figure 1). CD1a (Figure 2) and S-100 stains were markedly positive, which is characteristic of LCH. Complete blood cell count, renal function, liver function, urinalysis, and flow cytometry results were within reference range. A skeletal survey and echocardiogram were unremarkable; however, mild hepatosplenomegaly was noted on abdominal ultrasonography.

Treatment of LCH varies based on the extent of organ involvement. For isolated cutaneous disease, topical steroids, topical nitrogen mustard, phototherapy, and thalidomide may be employed.² Multisystem disease requires chemotherapeutic agents including vinblastine and prednisone.^2,3 Because more than half of patients with LCH have oncogenic BRAF V600E mutations,⁴ vemurafenib may have a therapeutic role in treatment. Rare case reports have documented disease response in patients with LCH and Erdheim-Chester disease.^5,6 

Prognosis varies based on age and extent of systemic involvement. Children younger than 2 years with multiorgan involvement have a poor prognosis (35%-55% mortality rate) compared to older children without hematopoietic, hepatosplenic, or lung involvement (100% survival rate). Additionally, response to treatment affects prognosis, as there is a 66% mortality rate in those who do not respond to treatment after 6 weeks.³ Long-term sequelae of LCH include endocrine dysfunction (ie, diabetes insipidus, growth hormone deficiencies), hearing impairment, orthopedic impairment, and neuropsychological disease; thus, multidisciplinary care often is neccessary.⁷

Given the multisystem involvement in our patient, he was treated with vinblastine, 6-mercaptopurine, and prednisolone with only partial and transient disease response. He was then treated with clofarabine with dramatic resolution of the mediastinal mass on follow-up positron emission tomography. The cutaneous lesions persisted and were managed with topical corticosteroids.