J Cutan Pathol 2015: 42: 295–296 doi: 10.1111/cup.12408 John Wiley & Sons. Printed in Singapore
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Letter to the Editor
Comments on ‘Generalized erythroderma and palmoplantar hyperkeratosis in a patient receiving TNF-alpha antagonist therapy’ Keywords: cutaneous T-cell lymphoma, erythroderma, peripheral blood, psoriasiform dermatitis, TNF-alpha To the Editor , Dunst-Huemer et al. recently published a case in the JCP that expanded the spectrum of cutaneous adverse reactions associated with anti-tumor necrosis factor (TNF)-alpha therapy. The patient developed generalized erythroderma with palmoplantar keratoderma after receiving TNF-alpha antagonist therapy for his long-standing psoriasis. Two skin biopsies showed psoriasiform inflammation with hyperkeratosis and parakeratosis and a perivascular lymphocytic infiltrate. Based on the skin biopsy results, a paradoxical drug eruption was diagnosed and assumed to represent an exacerbation of the underlying psoriasis by adalimumab. Upon discontinuation of adalimumab, the patient experienced quick improvement with topical glucocorticoids and oral antibiotics for a concomitant skin infection. Ustekinumab was initiated, but follow-up information was not provided.1 The differential diagnosis of generalized erythroderma is extensive, thus requiring a comprehensive work up. A patient’s clinical history may contribute in establishing the diagnosis and guiding the proper work up. In the given scenario of new erythroderma onset while on immunosuppressive therapy, besides a drug eruption, a lymphoproliferative disorder should be considered. While generalized erythroderma accounts for only approximately 5% of cutaneous T-cell lymphoma (CTCL) at presentation, its prevalence is higher when the disease
presents in the course of immunosuppressant treatments, especially calcineurin inhibitors and anti-TNF-alpha therapy.2,3 Regardless of the etiology, the histopathologic findings of erythroderma are often inconclusive with non-specific spongiosis and acanthosis. Moreover, only 55–65% of skin biopsies from patients with Sézary syndrome demonstrate histopathologic features that are diagnostic of CTCL.2,4 All erythrodermic patients, especially when CTCL is a diagnostic consideration, should undergo peripheral blood smear evaluation to exclude Sézary cells, preferably accompanied by immunophenotyping by flow cytometry and
Fig. 1. Extensive, confluent, erythematous and scaly plaques with a psoriasiform appearance involving the torso.
295
Letter to the Editor
Fig. 2. A) Histopathologic findings at low power (10×) show an acanthotic epidermis with parakeratosis and a lymphocytic infiltrate in the superficial dermis. The infiltrate is also prominent in the dermal papilla. B) High power view (20×) reveals neutrophilic exocytosis and a subcorneal pustule.
T-cell molecular clonality analysis. The morphology of Sézary cells is not entirely specific for CTCL, and a few abnormal cells comprising less than 10% of total lymphocytes may be observed in non-neoplastic erythroderma. Even these erythrodermic cases with apparently innocuous low SC or small populations of abnormal cells populations may develop complications. We recently evaluated an elderly woman at our clinic who presented with confluent erythematous and scaly plaques involving approximately 80% of the total body surface area. The clinical and histological impression was most consistent with erythrodermic psoriasis or pityriasis rubra pilaris (Figs. 1 and 2). However, the patient had failed common therapies for both conditions including methotrexate and acitretin and was worsening on phototherapy. The Sézary cell count was low with 20 cells/μl, and flow cytometry showed a small T-cell population negative for CD2, CD4 and CD8 comprising 7% of total cell events. Clonality assays revealed three distinct T cell clones variably present in skin and blood compartments. Because of the lack of CTCL features on skin biopsy, psoriasiform nature of the lesions, lack of monoclonality and the small number of abnormal cells on blood, the diagnosis of CTCL was not favored. Because of refractoriness of her cutaneous condition and severity of symptoms, an anti-TNF-alpha was prescribed. After a single dose of adalimumab, the patient developed worsening pruritus and
erythroderma, extensive lymphadenopathy and a marked increase of abnormal lymphocytes in blood reaching a leukemic count of 3578 cells. Expansion of the same abnormal T-cell population was now identified by flow cytometry on blood and nodal tissue. The phenotype was not typical for CTCL with negative CD2, CD4, CD8 and gamma–delta markers and positive expression of alpha–beta, CD7 and CD26. A diagnosis of peripheral T cell lymphoma with paraneoplastic psoriasiform dermatitis was established. The patient failed systemic chemotherapy, developed mental status changes and died shortly after. An autopsy showed extensive lymphoma involving the liver, lymph nodes and brain. Our case illustrates the importance of comprehensive blood assessment in erythrodermic patients, especially after immunosuppressive therapy. Furthermore, even a small population of abnormal cells may be highly significant and portent a grave outcome. Finally, we should emphasize that the diagnosis of generalized erythroderma may not be resolved simply with skin biopsies and that careful blood analysis may be required. Maria Estela Martinez-Escala, MD Joan Guitart, MD Departments of Dermatology and Pathology Northwestern University Feinberg Medical School Chicago, IL, USA e-mail: [email protected]
References C,
2. Nagler AR, Samimi S, Schaffer A, et al.
Auboeck J. Generalized erythroderma and
Peripheral blood findings in erythroder-
palmoplantar hyperkeratosis in a patient
mic patients: importance for the differential
receiving TNF-alpha antagonist therapy. J
diagnosis of Sezary syndrome. J Am Acad
Cutan Pathol 2013; 40: 855.
Dermatol 2012; 66: 503.
1. Dunst-Huemer
296
KM,
Scheurecker
3. Zattra E, Belloni Fortina A, Peserico A, et al. Erythroderma in the era of biological therapies. Eur J Dermatol 2012; 22: 167. 4. Zip C, Murray S, Walsh NM. The specificity of histopathology in erythroderma. J Cutan Pathol 1993; 20: 393.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Letter to the Editor
Comments on ‘Generalized erythroderma and palmoplantar hyperkeratosis in a patient receiving TNF-alpha antagonist therapy’ Keywords: cutaneous T-cell lymphoma, erythroderma, peripheral blood, psoriasiform dermatitis, TNF-alpha To the Editor , Dunst-Huemer et al. recently published a case in the JCP that expanded the spectrum of cutaneous adverse reactions associated with anti-tumor necrosis factor (TNF)-alpha therapy. The patient developed generalized erythroderma with palmoplantar keratoderma after receiving TNF-alpha antagonist therapy for his long-standing psoriasis. Two skin biopsies showed psoriasiform inflammation with hyperkeratosis and parakeratosis and a perivascular lymphocytic infiltrate. Based on the skin biopsy results, a paradoxical drug eruption was diagnosed and assumed to represent an exacerbation of the underlying psoriasis by adalimumab. Upon discontinuation of adalimumab, the patient experienced quick improvement with topical glucocorticoids and oral antibiotics for a concomitant skin infection. Ustekinumab was initiated, but follow-up information was not provided.1 The differential diagnosis of generalized erythroderma is extensive, thus requiring a comprehensive work up. A patient’s clinical history may contribute in establishing the diagnosis and guiding the proper work up. In the given scenario of new erythroderma onset while on immunosuppressive therapy, besides a drug eruption, a lymphoproliferative disorder should be considered. While generalized erythroderma accounts for only approximately 5% of cutaneous T-cell lymphoma (CTCL) at presentation, its prevalence is higher when the disease
presents in the course of immunosuppressant treatments, especially calcineurin inhibitors and anti-TNF-alpha therapy.2,3 Regardless of the etiology, the histopathologic findings of erythroderma are often inconclusive with non-specific spongiosis and acanthosis. Moreover, only 55–65% of skin biopsies from patients with Sézary syndrome demonstrate histopathologic features that are diagnostic of CTCL.2,4 All erythrodermic patients, especially when CTCL is a diagnostic consideration, should undergo peripheral blood smear evaluation to exclude Sézary cells, preferably accompanied by immunophenotyping by flow cytometry and
Fig. 1. Extensive, confluent, erythematous and scaly plaques with a psoriasiform appearance involving the torso.
295
Letter to the Editor
Fig. 2. A) Histopathologic findings at low power (10×) show an acanthotic epidermis with parakeratosis and a lymphocytic infiltrate in the superficial dermis. The infiltrate is also prominent in the dermal papilla. B) High power view (20×) reveals neutrophilic exocytosis and a subcorneal pustule.
T-cell molecular clonality analysis. The morphology of Sézary cells is not entirely specific for CTCL, and a few abnormal cells comprising less than 10% of total lymphocytes may be observed in non-neoplastic erythroderma. Even these erythrodermic cases with apparently innocuous low SC or small populations of abnormal cells populations may develop complications. We recently evaluated an elderly woman at our clinic who presented with confluent erythematous and scaly plaques involving approximately 80% of the total body surface area. The clinical and histological impression was most consistent with erythrodermic psoriasis or pityriasis rubra pilaris (Figs. 1 and 2). However, the patient had failed common therapies for both conditions including methotrexate and acitretin and was worsening on phototherapy. The Sézary cell count was low with 20 cells/μl, and flow cytometry showed a small T-cell population negative for CD2, CD4 and CD8 comprising 7% of total cell events. Clonality assays revealed three distinct T cell clones variably present in skin and blood compartments. Because of the lack of CTCL features on skin biopsy, psoriasiform nature of the lesions, lack of monoclonality and the small number of abnormal cells on blood, the diagnosis of CTCL was not favored. Because of refractoriness of her cutaneous condition and severity of symptoms, an anti-TNF-alpha was prescribed. After a single dose of adalimumab, the patient developed worsening pruritus and
erythroderma, extensive lymphadenopathy and a marked increase of abnormal lymphocytes in blood reaching a leukemic count of 3578 cells. Expansion of the same abnormal T-cell population was now identified by flow cytometry on blood and nodal tissue. The phenotype was not typical for CTCL with negative CD2, CD4, CD8 and gamma–delta markers and positive expression of alpha–beta, CD7 and CD26. A diagnosis of peripheral T cell lymphoma with paraneoplastic psoriasiform dermatitis was established. The patient failed systemic chemotherapy, developed mental status changes and died shortly after. An autopsy showed extensive lymphoma involving the liver, lymph nodes and brain. Our case illustrates the importance of comprehensive blood assessment in erythrodermic patients, especially after immunosuppressive therapy. Furthermore, even a small population of abnormal cells may be highly significant and portent a grave outcome. Finally, we should emphasize that the diagnosis of generalized erythroderma may not be resolved simply with skin biopsies and that careful blood analysis may be required. Maria Estela Martinez-Escala, MD Joan Guitart, MD Departments of Dermatology and Pathology Northwestern University Feinberg Medical School Chicago, IL, USA e-mail: [email protected]
References C,
2. Nagler AR, Samimi S, Schaffer A, et al.
Auboeck J. Generalized erythroderma and
Peripheral blood findings in erythroder-
palmoplantar hyperkeratosis in a patient
mic patients: importance for the differential
receiving TNF-alpha antagonist therapy. J
diagnosis of Sezary syndrome. J Am Acad
Cutan Pathol 2013; 40: 855.
Dermatol 2012; 66: 503.
1. Dunst-Huemer
296
KM,
Scheurecker
3. Zattra E, Belloni Fortina A, Peserico A, et al. Erythroderma in the era of biological therapies. Eur J Dermatol 2012; 22: 167. 4. Zip C, Murray S, Walsh NM. The specificity of histopathology in erythroderma. J Cutan Pathol 1993; 20: 393.
