- Email: [email protected]
T-cell large granular lymphocyte leukemia: A cause of complex aphthosis not to be missed
S60 Letters
J AM ACAD DERMATOL AUGUST 2007
Andre´’s Hospital, 1, Rue Jean Burguet, 33075 Bordeaux cedex, France E-mail: [email protected] REFERENCES 1. Sirvent N, Maire G, Pedeutour F. Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment. Genes Chromosomes Cancer 2003;37:1-19. 2. Maire G, Pedeutour F, Coindre JM. COL1A1-PDGFB gene fusion demonstrates a common histogenetic origin for dermatofibrosarcoma protuberans and its granular cell variant. Am J Surg Pathol 2002;7:932-7. 3. Coindre JM, Hostein I, Maire G, Derre´ J, Guillou L, Leroux A, et al. Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile and MDM2 and CDK4 status in favour of a single entity. J Pathol 2004;203:822-30. 4. Gardner TL, Elston DM, Wotowic PJ. A familial dermatofibrosarcoma protuberans. J Am Acad Dermatol 1998;39:504-5. 5. Harvell JD. Multiple spindle cell lipomas and dermatofibrosarcoma protuberans within a single patient: evidence for a common neoplastic process of interstitial dendritic cells? J Am Acad Dermatol 2003;48:82-5. doi:10.1016/j.jaad.2006.04.059
T-cell large granular lymphocyte leukemia: A cause of complex aphthosis not to be missed To the Editor: Letsinger, McCarthy, and Jorizzo1 recently reported on complex aphthosis, the diagnostic criteria of which are as follows: (1) almost constant presence of multiple ($3) oral ulcers, (2) recurrent oral and genital aphthae, and (3) exclusion of Behc¸et’s disease. We describe a patient with a case of T-cell large granular lymphocyte (LGL) leukemia associated with severe chronic neutropenia who presented with complex aphthosis. A 61-year-old woman presented with chronic oral ulcerations of 2 years’ duration accompanied by fever attacks with a periodicity of 14 to 21 days. Moreover, she had a 1-year history of rheumatoid arthritis. At examination she showed several more or less deep oral ulcerations (Fig 1). Pathergy test was negative. White and red blood cell counts, thrombocytes, and HLA-B51 were within the normal range or negative (Table I). She was HLA-DR4 positive and had elevated levels of the following: rheumatoid factor, 122 U/mL (reference range, 0-14 U/mL), IgG, 2070 mg (reference range, 700-1600 mg), circulating immune complexes 4 g (reference range, 0-1.5 g), and antinuclear antibodies, 1:640 (reference, \1:80). Immunophenotyping of peripheral blood mononuclear cells showed cells positive for CD3 (93.9%), CD8 (71.4%), CD57 (37%), and T-cell receptor (TCR)-a/b (68%). There was a biallelic TCR gene rearrangement of the CD81 T cells. Bone marrow
Fig 1. Chronically neutropenic patient with T-cell LGL leukemia with two mucosal ulcers of the upper lip of different size, partly covered by grayish fibromembranous slough surrounded by slight erythema and edema ([).
Table I. Blood test results of a patient with T-cell LGL leukemia and complex aphthosis* Parameter
Neutrophils CD81 cells CD4/CD8 ratio
Median (normal range)
320/L (1800-7200/L) 2188/L (190-1140/L) 0.49 (0.8-2.0)
Range
40-610/L 1490-2480/l 0.29-0.664
*Blood collections (N ¼ 12) were performed twice weekly over a 6-week period.
biopsy revealed a diffuse proliferation of the CD81 T cells. We initiated cyclosporine at 5 mg/kg per day, which significantly improved neutropenia and associated symptoms including complex aphthosis, despite the persistence of abnormal T cells. T-cell LGL leukemia is a rare hematologic condition characterized by increased numbers of circulating LGLs associated with chronic neutropenia. Patients with T cell LGL leukemia usually have either normal absolute lymphocyte counts or a mild lymphocytosis. Inversion of the CD4/CD8 ratio is frequently observed in these patients. The diagnosis of T-cell LGL leukemia is suggested by flow cytometry demonstrating an expansion of CD31/CD81/CD571 T cells and is confirmed by monoclonal TCR gene rearrangement studies. Biallelic TCR rearrangement, as observed in our patient, is unusual. The association with rheumatoid arthritis and autoimmune phenomena such as antinuclear antibodies, circulating immune complexes, and hypergammaglobulinemia, has been well documented in patients with T-cell LGL leukemia.2,3 The latter, which predominantly affects the elderly, is generally clinically indolent. Nevertheless, approximately 50% of patients with LGL expansions have severe neutropenia, which renders them susceptible to life-threatening infections. Felty’s syndrome is a very closely related
Letters S61
J AM ACAD DERMATOL VOLUME 57, NUMBER 2
condition comprising a triad of severe rheumatoid arthritis, neutropenia, and splenomegaly.3 Chronic neutropenia can be a rare complication of Behc¸et’s disease, which is usually characterized by symptoms including oral and genital aphthous ulcers, uveitis, skin lesions, positive pathergy test, and a high prevalence of HLA-B51.4 The periodicity of fever attacks observed in the present case may indicate adult-onset cyclic neutropenia, which is clinically characterized by recurrent episodes of oral aphthae, fever, and malaise with a periodicity of approximately 21 days. Between the episodes, however, patients with cyclic neutropenia are usually in complete clinical and laboratory remission.5 Interestingly, oral ulcers are observed only in approximately 5% of patients with T-cell LGL leukemia despite severe neutropenia.2 Nevertheless, T-cell LGL leukemia should not be missed as a possible cause of complex aphthosis. Thilo Gambichler, MD, Stephan Ho¨xtermann, PhD, and Peter Altmeyer, MD Department of Dermatology, Bochum, Bochum, Germany
Ruhr-University
Funding sources: None. Conflict of interest: None declared. Correspondence to: Thilo Gambichler, MD, Department of Dermatology, Ruhr-University Bochum, Gudrunstr 56, 44791 Bochum, Germany E-mail: [email protected] REFERENCES 1. Letsinger JA, McCarthy MA, Jorizzo JL. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J Am Acad Dermatol 2005; 52:500-8. 2. Semenzato G, Zambello R, Starkebaum, Oshimi K, Loughran TP Jr. The lymphoproliferative disease of large granular lymphocytes: updated criteria for diagnosis. Blood 1997;89:256-60. 3. Rose MG, Berliner N. T-cell large granular lymphocyte leukemia and related disorders. Oncologist 2004;9:247-58. 4. Demiroglu H, Dundar S. Behcet’s disease and chronic neutropenia. Scand J Rheumatol 1997;26:130-2. 5. Berliner N, Horwitz M, Loughran TP Jr. Congenital and acquired neutropenia. Hematology (Am Soc Hematol Educ Program) 2004. pp. 63-79. doi:10.1016/j.jaad.2006.04.016
Acute generalized exanthematous pustulosis (AGEP) after oral use of amphotericin B To the Editor: A recent paper in the British Journal of Dermatology reported acute generalized exanthematous pustulosis (AGEP) induced by terbinafine.1 We would like to report AGEP after oral
amphotericine B. The list of antimycotic drugs reported to induce AGEP includes terbinafine, itraconazole, fluconazol, griseofulvine nystatin, and now amphotericin B. A 68-year-old male was admitted to our department with a generalized pustular exanthem. His past medical history was significant for multiple general medical problems. He suffered from organic brain syndrome caused by several strokes and had had an excision of a meningeoma 5 months before presentation. His long-term medications had not been changed within the last 3 months and consisted of verapamil, ramipril, ranitidine, phenhydane, novalgin, metformin, haloperidol, furosemide, bisoprolol, allopurinol, and dexamethasone (4 mg/d). Amphotericin B suspension had been prescribed 3 weeks previously for the treatment of oral candidosis. The patient presented with generalized, confluent, erythematous macules covered with close-standing small, subcorneal pustules (Fig 1). The exanthem was more prominent in the flexural areas and showed active borders. The patient had no fever. Laboratory investigation revealed leukocytosis (22.3 3 109/L) and an increase of g-glutamyl-transferase (10.5 mol/L) but was otherwise unremarkable. No bacteria or fungi were found from a culture of pustule contents. A skin biopsy from the thigh showed slight acanthosis and distinct subcorneal pustules filled with neutrophils. There was a sparse perivascular and interstitial lymphocytic infiltrate in the papillary dermis (Fig 2). Periodic acideSchiff stain was negative for fungi. Upon hospitalization, amphotericin B was discontinued. The patient was treated with topical corticosteroids, and the skin lesions improved dramatically. After a few days of treatment the patient was discharged to a nursing home with near complete resolution of his skin lesions. One week later he was readmitted with an extensive reexacerbation of the rash. Amphotericin B suspension had been unknowingly readministered for treatment of oral candidosis. After discontinuing amphotericin B, systemic therapy with prednisolone (60 mg/d) was initiated with prompt clearing of the patient’s rash. During a follow-up of several months, the patient’s skin remained normal. The exact mechanism of AGEP is unknown. In cultured peripheral blood, mononuclear cells from patients with AGEP drug-specific T-cell clones expressing the neutrophil-attracting chemokine IL-8 could be identified.2 Some clinicians perform prick and patch testing for diagnosis. Positive results, however, have only been reported in a minority of patients.4 In this case, prick and patch testing with amphothericin B and nystatin (as a related substance)
J AM ACAD DERMATOL AUGUST 2007
Andre´’s Hospital, 1, Rue Jean Burguet, 33075 Bordeaux cedex, France E-mail: [email protected] REFERENCES 1. Sirvent N, Maire G, Pedeutour F. Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment. Genes Chromosomes Cancer 2003;37:1-19. 2. Maire G, Pedeutour F, Coindre JM. COL1A1-PDGFB gene fusion demonstrates a common histogenetic origin for dermatofibrosarcoma protuberans and its granular cell variant. Am J Surg Pathol 2002;7:932-7. 3. Coindre JM, Hostein I, Maire G, Derre´ J, Guillou L, Leroux A, et al. Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile and MDM2 and CDK4 status in favour of a single entity. J Pathol 2004;203:822-30. 4. Gardner TL, Elston DM, Wotowic PJ. A familial dermatofibrosarcoma protuberans. J Am Acad Dermatol 1998;39:504-5. 5. Harvell JD. Multiple spindle cell lipomas and dermatofibrosarcoma protuberans within a single patient: evidence for a common neoplastic process of interstitial dendritic cells? J Am Acad Dermatol 2003;48:82-5. doi:10.1016/j.jaad.2006.04.059
T-cell large granular lymphocyte leukemia: A cause of complex aphthosis not to be missed To the Editor: Letsinger, McCarthy, and Jorizzo1 recently reported on complex aphthosis, the diagnostic criteria of which are as follows: (1) almost constant presence of multiple ($3) oral ulcers, (2) recurrent oral and genital aphthae, and (3) exclusion of Behc¸et’s disease. We describe a patient with a case of T-cell large granular lymphocyte (LGL) leukemia associated with severe chronic neutropenia who presented with complex aphthosis. A 61-year-old woman presented with chronic oral ulcerations of 2 years’ duration accompanied by fever attacks with a periodicity of 14 to 21 days. Moreover, she had a 1-year history of rheumatoid arthritis. At examination she showed several more or less deep oral ulcerations (Fig 1). Pathergy test was negative. White and red blood cell counts, thrombocytes, and HLA-B51 were within the normal range or negative (Table I). She was HLA-DR4 positive and had elevated levels of the following: rheumatoid factor, 122 U/mL (reference range, 0-14 U/mL), IgG, 2070 mg (reference range, 700-1600 mg), circulating immune complexes 4 g (reference range, 0-1.5 g), and antinuclear antibodies, 1:640 (reference, \1:80). Immunophenotyping of peripheral blood mononuclear cells showed cells positive for CD3 (93.9%), CD8 (71.4%), CD57 (37%), and T-cell receptor (TCR)-a/b (68%). There was a biallelic TCR gene rearrangement of the CD81 T cells. Bone marrow
Fig 1. Chronically neutropenic patient with T-cell LGL leukemia with two mucosal ulcers of the upper lip of different size, partly covered by grayish fibromembranous slough surrounded by slight erythema and edema ([).
Table I. Blood test results of a patient with T-cell LGL leukemia and complex aphthosis* Parameter
Neutrophils CD81 cells CD4/CD8 ratio
Median (normal range)
320/L (1800-7200/L) 2188/L (190-1140/L) 0.49 (0.8-2.0)
Range
40-610/L 1490-2480/l 0.29-0.664
*Blood collections (N ¼ 12) were performed twice weekly over a 6-week period.
biopsy revealed a diffuse proliferation of the CD81 T cells. We initiated cyclosporine at 5 mg/kg per day, which significantly improved neutropenia and associated symptoms including complex aphthosis, despite the persistence of abnormal T cells. T-cell LGL leukemia is a rare hematologic condition characterized by increased numbers of circulating LGLs associated with chronic neutropenia. Patients with T cell LGL leukemia usually have either normal absolute lymphocyte counts or a mild lymphocytosis. Inversion of the CD4/CD8 ratio is frequently observed in these patients. The diagnosis of T-cell LGL leukemia is suggested by flow cytometry demonstrating an expansion of CD31/CD81/CD571 T cells and is confirmed by monoclonal TCR gene rearrangement studies. Biallelic TCR rearrangement, as observed in our patient, is unusual. The association with rheumatoid arthritis and autoimmune phenomena such as antinuclear antibodies, circulating immune complexes, and hypergammaglobulinemia, has been well documented in patients with T-cell LGL leukemia.2,3 The latter, which predominantly affects the elderly, is generally clinically indolent. Nevertheless, approximately 50% of patients with LGL expansions have severe neutropenia, which renders them susceptible to life-threatening infections. Felty’s syndrome is a very closely related
Letters S61
J AM ACAD DERMATOL VOLUME 57, NUMBER 2
condition comprising a triad of severe rheumatoid arthritis, neutropenia, and splenomegaly.3 Chronic neutropenia can be a rare complication of Behc¸et’s disease, which is usually characterized by symptoms including oral and genital aphthous ulcers, uveitis, skin lesions, positive pathergy test, and a high prevalence of HLA-B51.4 The periodicity of fever attacks observed in the present case may indicate adult-onset cyclic neutropenia, which is clinically characterized by recurrent episodes of oral aphthae, fever, and malaise with a periodicity of approximately 21 days. Between the episodes, however, patients with cyclic neutropenia are usually in complete clinical and laboratory remission.5 Interestingly, oral ulcers are observed only in approximately 5% of patients with T-cell LGL leukemia despite severe neutropenia.2 Nevertheless, T-cell LGL leukemia should not be missed as a possible cause of complex aphthosis. Thilo Gambichler, MD, Stephan Ho¨xtermann, PhD, and Peter Altmeyer, MD Department of Dermatology, Bochum, Bochum, Germany
Ruhr-University
Funding sources: None. Conflict of interest: None declared. Correspondence to: Thilo Gambichler, MD, Department of Dermatology, Ruhr-University Bochum, Gudrunstr 56, 44791 Bochum, Germany E-mail: [email protected] REFERENCES 1. Letsinger JA, McCarthy MA, Jorizzo JL. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J Am Acad Dermatol 2005; 52:500-8. 2. Semenzato G, Zambello R, Starkebaum, Oshimi K, Loughran TP Jr. The lymphoproliferative disease of large granular lymphocytes: updated criteria for diagnosis. Blood 1997;89:256-60. 3. Rose MG, Berliner N. T-cell large granular lymphocyte leukemia and related disorders. Oncologist 2004;9:247-58. 4. Demiroglu H, Dundar S. Behcet’s disease and chronic neutropenia. Scand J Rheumatol 1997;26:130-2. 5. Berliner N, Horwitz M, Loughran TP Jr. Congenital and acquired neutropenia. Hematology (Am Soc Hematol Educ Program) 2004. pp. 63-79. doi:10.1016/j.jaad.2006.04.016
Acute generalized exanthematous pustulosis (AGEP) after oral use of amphotericin B To the Editor: A recent paper in the British Journal of Dermatology reported acute generalized exanthematous pustulosis (AGEP) induced by terbinafine.1 We would like to report AGEP after oral
amphotericine B. The list of antimycotic drugs reported to induce AGEP includes terbinafine, itraconazole, fluconazol, griseofulvine nystatin, and now amphotericin B. A 68-year-old male was admitted to our department with a generalized pustular exanthem. His past medical history was significant for multiple general medical problems. He suffered from organic brain syndrome caused by several strokes and had had an excision of a meningeoma 5 months before presentation. His long-term medications had not been changed within the last 3 months and consisted of verapamil, ramipril, ranitidine, phenhydane, novalgin, metformin, haloperidol, furosemide, bisoprolol, allopurinol, and dexamethasone (4 mg/d). Amphotericin B suspension had been prescribed 3 weeks previously for the treatment of oral candidosis. The patient presented with generalized, confluent, erythematous macules covered with close-standing small, subcorneal pustules (Fig 1). The exanthem was more prominent in the flexural areas and showed active borders. The patient had no fever. Laboratory investigation revealed leukocytosis (22.3 3 109/L) and an increase of g-glutamyl-transferase (10.5 mol/L) but was otherwise unremarkable. No bacteria or fungi were found from a culture of pustule contents. A skin biopsy from the thigh showed slight acanthosis and distinct subcorneal pustules filled with neutrophils. There was a sparse perivascular and interstitial lymphocytic infiltrate in the papillary dermis (Fig 2). Periodic acideSchiff stain was negative for fungi. Upon hospitalization, amphotericin B was discontinued. The patient was treated with topical corticosteroids, and the skin lesions improved dramatically. After a few days of treatment the patient was discharged to a nursing home with near complete resolution of his skin lesions. One week later he was readmitted with an extensive reexacerbation of the rash. Amphotericin B suspension had been unknowingly readministered for treatment of oral candidosis. After discontinuing amphotericin B, systemic therapy with prednisolone (60 mg/d) was initiated with prompt clearing of the patient’s rash. During a follow-up of several months, the patient’s skin remained normal. The exact mechanism of AGEP is unknown. In cultured peripheral blood, mononuclear cells from patients with AGEP drug-specific T-cell clones expressing the neutrophil-attracting chemokine IL-8 could be identified.2 Some clinicians perform prick and patch testing for diagnosis. Positive results, however, have only been reported in a minority of patients.4 In this case, prick and patch testing with amphothericin B and nystatin (as a related substance)