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Cutaneous and neurologic disease associated with HTLV-I infection
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Cutaneous and neurologic disease associated with HTLV-I infection Harry H. Sharata, MD, PhD, a Jill Hatfield Colvin, a K. Fujiwara, MD, b Barry Goldman, M D , c and Ken Hashimoto, M D b Madison, Wisconsin; Detroit, Michigan; and
New York, New York Human T-lymphotropic virus type I (HTLV-I) is the etiologic agent of HTLV-I associated myelopathy (HAM)/tropical spastic paresis (TSP), and adult T-cell leukemia/lymphoma (ATLL). ATLL has been associated with HTLV-I in the southeastern United States. However, to our knowledge, no case reports of HAM/TSP in association with ATLL occurring in the United States have been described. We describe a 40-year-old black woman with a 10year history of recalcitrant psoriasiform eruption and erythrodermic flares. Medical history is additionally significant for a 2-year history of HTLV-I-associated myelopathy and lower extremity spastic paresis. Polymerase chain reaction with Southern blot analysis was used to detect HTLV-I proviral genome from frozen skin biopsy specimens and peripheral blood mononuclear cells. (J Am Acad Dermatol 1997;36:869-71.) Human T-lymphotropic virus type I (HTLV-I) is the cause of HTLV-I-associated myelopathy (HAM)/tropical spastic paresis (TSP),I and adult Tcell leukemia/lymphoma (ATLL). 2 HTLV-I infection and A T L L are endemic in southwestern Japan, the Caribbean region, Central and South America, and some parts of Africa. Infection with HTLV-I was thought to be rare in the United States. However, recent studies of prostitutes in the United States revealed up to 25.4% seropositivity, independently associated with race (black, Hispanic, Native American), intravenous drug use, and hepatitis B seropositivity. 3 The American Red Cross has documented 0.025% HTLV-I seropositivity among U.S. volunteer blood donors. 4 A T L L has been associated with HTLV-I in the southeastern United States. However, to our knowledge, no case reports of H A M / T S P in association with A T L L occurring in the United States have been described. Two such patients have This article is made possible through an educational grant from the Dermatological Division, Ortho Pharmaceutical Corporation. From tile Dermatology Clinic, University of Wisconsin Hospital and Clinics, Madison, a the Department of Dermatology, Wayne State University School of Medicine, Detroit, b and the Department of Demaatology, New York University, New York. Presented in part at the 1994 Annual Meeting of the Society for Investigative Dermatology, Baltimore, Md., April 27-30, 1994. *Reprint requests: Harry H. Sharata, MD, PhD, University Station Clinics, 2880 University Ave. Madison, WI 53705. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97155.00 + 0 1614/78246 ORTI-IO
been described in an endemic area of Japan, 5, 6 and another in an adult patient from Guatemala residing in the U.K. 7 We describe the first American patient to exhibit both cutaneous and neurologic disease resulting from or exacerbated by HTLV-I infection. 8 CASE REPORT
A 40-year-old black woman had a 10-year history of recalcitrant psoriasis and erythrodermic flares resistant to treatment with topical steroids, Goeckerman therapy, and etretinate combined with PUVA. Because of her hepatitis B and C seropositivity she was not considered an appropriate candidate for methotrexate. She also had a 2-year history of HAM and lower extremity TSP. This diagnosis was based on HTLV-FII antibodies in both serum and cerebrospinal fluid with normal brain magnetic resonance imaging and myelograrn, normal B-12 level, and negative evaluation for other secondary causes of myelopathy. Her medications were oral baclofen 25 mg three times dally and prednisone 20 mg every other day. She has shown gradual improvement in her gait since instituting these medications. Examination revealed generalized erythroderma (Fig. 1), pitting of nails, distal onycholysis, bilateral lower extremity spasticity with ataxia, and inguinal and axillary lymphadenopathy. Laboratory studies revealed mild anemia, normal white blood cells and differential, normal serum protein electrophoresis, normal serum calcium, normal lactate dehydrogenase, and negative HIV. No Sezary cells were identiffed in a huffy coat preparation. Chest roentgenogram and a bone marrow biopsy specimen were normal. 869
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Sharata et al.
Journal of the American Academy of Dermatology May 1997
Fig. 1. Generalized erythroderma and scaling.
An inguinal lymph node biopsy specimen revealed dermatopathic lymphadenopathy. Skin biopsy specimens revealed a psoriasiform dermatitis with a heavy lymphohistiocytic infiltrate. Immunohistochemistry studies were performed on fresh frozen sections of skin using the immunoperoxidase method. Immunophenotyping revealed a high percentage (75%) of CD3/CD4/CD1 IcAtLA-DR+ cells with 25% to 50% CD25 (IL-2 receptor) expression (Table I). Polymerase chain reaction was performed on peripheral blood leukocytes and a frozen skin biopsy specimen by means of primers designed to match the HTLV-I specific proviral pol and gag genome, as described by Hall et al. in 1991.9 Southern blot analysis was used to study polymerase chain reaction products. Southern blots revealed that the patient's peripheral blood mononuclear cells and skin cells contained the gag and pol regions of the proviral HTLV-I genome, whereas normal control skin was negative for gag and pol regions of HTLV-I proviral genome, and positive control reacted appropriately (Fig. 2).
DISCUSSION Our patient had many risk factors for acquiring HTLV-I such as previous blood transfusions, hepatitis B infection, multiple sexual partners, and intravenous drug use with needle-sharing. ATLL shares clinicopathologic features with various types of cutaneous T-cell lymphoma. ATLL and mycosis fungoides share the same T cell phenotype (CD30-, CD45RO +, CD4 +). 10Pancake, Zucker-Franklin, and Coutavas et al.ll suggested that mycosis fungoides (MF) is an HTLV-I-associated disease because of the discovery that 92% of 50 MF patients (from New York) have HTLV-I pol or tax genome in blood mononuclear cells. 11
Fig. 2. Southern analysis of polymerase chain reaction (PCR) products (PCR primers: A, gag and B, pol region HTLV-I proviral genome). Lane 1: Lymphocyte DNA from HTLV-I seronegative control; lane 2: positive control (HTLV-I infected celMine); lane 3: patient's bloodderived DNA; lane 4: patient's skin-derived DNA.
It is generally accepted that positivity for HTLV-I D N A in a skin biopsy specimen is diagnostic of the cutaneous form of ATLL. 12' 13 Five clinical types of ATLL have been identified: acute, lymphocytic, chronic, smoldering, and acute exacerbation (crisis) of any one of these. Cutaneous manifestations of ATLL include leukocytolastic purpura, MF-like plaque/tumor, Sezarylike erythroderma, and a papulosquamous eruption (psoriasiform presentation). The smoldering type of ATLL is
Journal of the American Academy of Dermatology Volume 36, Number 5, Part 2
Sharata et al.
871
I . I m m u n o p h e n o t y p i n g o f the c u t a n e o u s infiltrate: S e l e c t e d a n t i b o d i e s , their specificites, a n d r e a c t i o n in c u t a n e o u s infiltrate o f c a s e - s t u d y p a t i e n t Table
Antibody
Differentiation cluster
Specificity
Reaction*
Leu 2a Leu 3a Leu 4 Leu M5 Leu 8 Leu 9 Leu 14 Tac Ki-1 Ki-67 HLA-DR
CD8 CD4 CD3 CD1 l c CD7 CD22 CD25 CD30 -
Cytotoxic T cells Helper T cells Pan-T cells Monocyte, macrophage, granulocyte T cell, B cell, granulocyte, monocyte Pan-T cells B cell Activated T cells Reed-Sternberg cells Cells in mitotic cycle B cells, activated T cells, monocytes
++ +++ +++ +++ ++ ++ _+ + +++
*Each + equals 25% of infiltrate stained.
c h a r a c t e r i z e d b y s k i n l e s i o n s infiltrated w i t h T-cells, a l o w r u m o r load, a n d a s l o w e v o l u t i o n . 14 W h i t t a k e r et at. t2 p r o p o s e d that c u t a n e o u s a d u l t T - c e l l l y m phoma can exist distinct from classical ATLL and c a n h a v e a b e t t e r p r o g n o s i s . 12 It is l i k e l y that o u r p a tient b e s t fits into the d i a g n o s t i c c a t e g o r y o f s m o l dering ATLL with erythrodermic and psoriasiform characteristics and HAM/TSP resulting from H T L V - I infection. S h e is the first A m e r i c a n p a t i e n t d o c u m e n t e d to e x h i b i t b o t h c u t a n e o u s a n d n e u r o logic disease resulting from, or exacerbated by, H T L V - I infection. REFERENCES
1. Osame M, UsukqJ K, Izumo S, et al. HTLV-I associated myelopathy, a new clinical entity. Lancet 1986; 1:1031-2. 2. Gessain A, Moulongeut I, Flageul B, et al. Cutaneous type of adult T cell leukemia/lymphoma in a French West Indian Woman. J Am Acad Dermatol 1990;23:994-1000. 3. Kahabbaz R, Darrow W, Hartley T, et al. Seroprevalence and risk factors for HTLV-I/II infection among female prostitutes in the United States. JAMA 1990;263:60-4. 4. Williams A, Fang C, Slamon D, et al. Seroprevalence and epidemiological correlates of HTLV-I infection in U.S. blood donors. Science 1988;240:643-6. 5. Yasui C, Fukaya T, Koizumi H, et al. HTLV-I-associated myelopathy in a patient with adult T-cell leukemia. J Am Acad Dermatol 1991 ;24:633-7.
6. Kuwabara H, Katanaka J, Nagai M, et al. Human T lymphotropic virus type I associated myelopathy with pulmonary and cutaneous lesions. J Clin Pathol 1993;46:273-5. 7. Arai E, Chow K, Li C, et al. Differentiation between cutaneous form of adult T cell leukemia/lymphoma and cutaneous T cell lymphoma by in situ hybridization using a human T cell leukemia vims-I DNA probe. Am J Pathol 1994;144:15-20. 8. Sharata H, Fujiwara K, Goldman B, et al. Detection of HTLV-I DNA in an erythrodermic woman. SID Abstract. J Invest Dermatol 1994;102:543. 9. Hall W, Liu C, Schneewind O, et al. Deleted HTLV-I provims in blood and cutaneous lesions of patients with mycosis fungoides. Science 1991;253:317-20. 10. Nagatani T, Matsuzaki T, Iemoto G, et al. Comparative study of cutaneous T cell lymphoma and adult T cell leukemia lymphoma. Cancer 1990;66:2380-6. 11. Pancake B, Zucker-Franklin D, Coutavas E. The cutaneous T cell lymphoma, mycosis fungoides, is a human T cell lymphotropic vires-associated disease. J Clin Invest 1995;95:547-54. 12. Whittaker S, Ng Y, Rustin M, et al. HTLV-I-associated cutaneous disease: a clinicopathological and molecular study of patients from the U.K. Br J Dermatol 1993; 128:483-92. 13. Detmar M, Panli G, Anagnostopoulos I, et al. A case of classical mycosis fungoides associated with human T-cell lymphotropic virus type I. Br J Dermatol 1991;124:198202. 14. Kawano F, Yamaguchi K, Nishimura H, et al. Variation in the clinical courses of adult T cell leukemia. Cancer 1985; 55:851-6.
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Cutaneous and neurologic disease associated with HTLV-I infection Harry H. Sharata, MD, PhD, a Jill Hatfield Colvin, a K. Fujiwara, MD, b Barry Goldman, M D , c and Ken Hashimoto, M D b Madison, Wisconsin; Detroit, Michigan; and
New York, New York Human T-lymphotropic virus type I (HTLV-I) is the etiologic agent of HTLV-I associated myelopathy (HAM)/tropical spastic paresis (TSP), and adult T-cell leukemia/lymphoma (ATLL). ATLL has been associated with HTLV-I in the southeastern United States. However, to our knowledge, no case reports of HAM/TSP in association with ATLL occurring in the United States have been described. We describe a 40-year-old black woman with a 10year history of recalcitrant psoriasiform eruption and erythrodermic flares. Medical history is additionally significant for a 2-year history of HTLV-I-associated myelopathy and lower extremity spastic paresis. Polymerase chain reaction with Southern blot analysis was used to detect HTLV-I proviral genome from frozen skin biopsy specimens and peripheral blood mononuclear cells. (J Am Acad Dermatol 1997;36:869-71.) Human T-lymphotropic virus type I (HTLV-I) is the cause of HTLV-I-associated myelopathy (HAM)/tropical spastic paresis (TSP),I and adult Tcell leukemia/lymphoma (ATLL). 2 HTLV-I infection and A T L L are endemic in southwestern Japan, the Caribbean region, Central and South America, and some parts of Africa. Infection with HTLV-I was thought to be rare in the United States. However, recent studies of prostitutes in the United States revealed up to 25.4% seropositivity, independently associated with race (black, Hispanic, Native American), intravenous drug use, and hepatitis B seropositivity. 3 The American Red Cross has documented 0.025% HTLV-I seropositivity among U.S. volunteer blood donors. 4 A T L L has been associated with HTLV-I in the southeastern United States. However, to our knowledge, no case reports of H A M / T S P in association with A T L L occurring in the United States have been described. Two such patients have This article is made possible through an educational grant from the Dermatological Division, Ortho Pharmaceutical Corporation. From tile Dermatology Clinic, University of Wisconsin Hospital and Clinics, Madison, a the Department of Dermatology, Wayne State University School of Medicine, Detroit, b and the Department of Demaatology, New York University, New York. Presented in part at the 1994 Annual Meeting of the Society for Investigative Dermatology, Baltimore, Md., April 27-30, 1994. *Reprint requests: Harry H. Sharata, MD, PhD, University Station Clinics, 2880 University Ave. Madison, WI 53705. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97155.00 + 0 1614/78246 ORTI-IO
been described in an endemic area of Japan, 5, 6 and another in an adult patient from Guatemala residing in the U.K. 7 We describe the first American patient to exhibit both cutaneous and neurologic disease resulting from or exacerbated by HTLV-I infection. 8 CASE REPORT
A 40-year-old black woman had a 10-year history of recalcitrant psoriasis and erythrodermic flares resistant to treatment with topical steroids, Goeckerman therapy, and etretinate combined with PUVA. Because of her hepatitis B and C seropositivity she was not considered an appropriate candidate for methotrexate. She also had a 2-year history of HAM and lower extremity TSP. This diagnosis was based on HTLV-FII antibodies in both serum and cerebrospinal fluid with normal brain magnetic resonance imaging and myelograrn, normal B-12 level, and negative evaluation for other secondary causes of myelopathy. Her medications were oral baclofen 25 mg three times dally and prednisone 20 mg every other day. She has shown gradual improvement in her gait since instituting these medications. Examination revealed generalized erythroderma (Fig. 1), pitting of nails, distal onycholysis, bilateral lower extremity spasticity with ataxia, and inguinal and axillary lymphadenopathy. Laboratory studies revealed mild anemia, normal white blood cells and differential, normal serum protein electrophoresis, normal serum calcium, normal lactate dehydrogenase, and negative HIV. No Sezary cells were identiffed in a huffy coat preparation. Chest roentgenogram and a bone marrow biopsy specimen were normal. 869
870
Sharata et al.
Journal of the American Academy of Dermatology May 1997
Fig. 1. Generalized erythroderma and scaling.
An inguinal lymph node biopsy specimen revealed dermatopathic lymphadenopathy. Skin biopsy specimens revealed a psoriasiform dermatitis with a heavy lymphohistiocytic infiltrate. Immunohistochemistry studies were performed on fresh frozen sections of skin using the immunoperoxidase method. Immunophenotyping revealed a high percentage (75%) of CD3/CD4/CD1 IcAtLA-DR+ cells with 25% to 50% CD25 (IL-2 receptor) expression (Table I). Polymerase chain reaction was performed on peripheral blood leukocytes and a frozen skin biopsy specimen by means of primers designed to match the HTLV-I specific proviral pol and gag genome, as described by Hall et al. in 1991.9 Southern blot analysis was used to study polymerase chain reaction products. Southern blots revealed that the patient's peripheral blood mononuclear cells and skin cells contained the gag and pol regions of the proviral HTLV-I genome, whereas normal control skin was negative for gag and pol regions of HTLV-I proviral genome, and positive control reacted appropriately (Fig. 2).
DISCUSSION Our patient had many risk factors for acquiring HTLV-I such as previous blood transfusions, hepatitis B infection, multiple sexual partners, and intravenous drug use with needle-sharing. ATLL shares clinicopathologic features with various types of cutaneous T-cell lymphoma. ATLL and mycosis fungoides share the same T cell phenotype (CD30-, CD45RO +, CD4 +). 10Pancake, Zucker-Franklin, and Coutavas et al.ll suggested that mycosis fungoides (MF) is an HTLV-I-associated disease because of the discovery that 92% of 50 MF patients (from New York) have HTLV-I pol or tax genome in blood mononuclear cells. 11
Fig. 2. Southern analysis of polymerase chain reaction (PCR) products (PCR primers: A, gag and B, pol region HTLV-I proviral genome). Lane 1: Lymphocyte DNA from HTLV-I seronegative control; lane 2: positive control (HTLV-I infected celMine); lane 3: patient's bloodderived DNA; lane 4: patient's skin-derived DNA.
It is generally accepted that positivity for HTLV-I D N A in a skin biopsy specimen is diagnostic of the cutaneous form of ATLL. 12' 13 Five clinical types of ATLL have been identified: acute, lymphocytic, chronic, smoldering, and acute exacerbation (crisis) of any one of these. Cutaneous manifestations of ATLL include leukocytolastic purpura, MF-like plaque/tumor, Sezarylike erythroderma, and a papulosquamous eruption (psoriasiform presentation). The smoldering type of ATLL is
Journal of the American Academy of Dermatology Volume 36, Number 5, Part 2
Sharata et al.
871
I . I m m u n o p h e n o t y p i n g o f the c u t a n e o u s infiltrate: S e l e c t e d a n t i b o d i e s , their specificites, a n d r e a c t i o n in c u t a n e o u s infiltrate o f c a s e - s t u d y p a t i e n t Table
Antibody
Differentiation cluster
Specificity
Reaction*
Leu 2a Leu 3a Leu 4 Leu M5 Leu 8 Leu 9 Leu 14 Tac Ki-1 Ki-67 HLA-DR
CD8 CD4 CD3 CD1 l c CD7 CD22 CD25 CD30 -
Cytotoxic T cells Helper T cells Pan-T cells Monocyte, macrophage, granulocyte T cell, B cell, granulocyte, monocyte Pan-T cells B cell Activated T cells Reed-Sternberg cells Cells in mitotic cycle B cells, activated T cells, monocytes
++ +++ +++ +++ ++ ++ _+ + +++
*Each + equals 25% of infiltrate stained.
c h a r a c t e r i z e d b y s k i n l e s i o n s infiltrated w i t h T-cells, a l o w r u m o r load, a n d a s l o w e v o l u t i o n . 14 W h i t t a k e r et at. t2 p r o p o s e d that c u t a n e o u s a d u l t T - c e l l l y m phoma can exist distinct from classical ATLL and c a n h a v e a b e t t e r p r o g n o s i s . 12 It is l i k e l y that o u r p a tient b e s t fits into the d i a g n o s t i c c a t e g o r y o f s m o l dering ATLL with erythrodermic and psoriasiform characteristics and HAM/TSP resulting from H T L V - I infection. S h e is the first A m e r i c a n p a t i e n t d o c u m e n t e d to e x h i b i t b o t h c u t a n e o u s a n d n e u r o logic disease resulting from, or exacerbated by, H T L V - I infection. REFERENCES
1. Osame M, UsukqJ K, Izumo S, et al. HTLV-I associated myelopathy, a new clinical entity. Lancet 1986; 1:1031-2. 2. Gessain A, Moulongeut I, Flageul B, et al. Cutaneous type of adult T cell leukemia/lymphoma in a French West Indian Woman. J Am Acad Dermatol 1990;23:994-1000. 3. Kahabbaz R, Darrow W, Hartley T, et al. Seroprevalence and risk factors for HTLV-I/II infection among female prostitutes in the United States. JAMA 1990;263:60-4. 4. Williams A, Fang C, Slamon D, et al. Seroprevalence and epidemiological correlates of HTLV-I infection in U.S. blood donors. Science 1988;240:643-6. 5. Yasui C, Fukaya T, Koizumi H, et al. HTLV-I-associated myelopathy in a patient with adult T-cell leukemia. J Am Acad Dermatol 1991 ;24:633-7.
6. Kuwabara H, Katanaka J, Nagai M, et al. Human T lymphotropic virus type I associated myelopathy with pulmonary and cutaneous lesions. J Clin Pathol 1993;46:273-5. 7. Arai E, Chow K, Li C, et al. Differentiation between cutaneous form of adult T cell leukemia/lymphoma and cutaneous T cell lymphoma by in situ hybridization using a human T cell leukemia vims-I DNA probe. Am J Pathol 1994;144:15-20. 8. Sharata H, Fujiwara K, Goldman B, et al. Detection of HTLV-I DNA in an erythrodermic woman. SID Abstract. J Invest Dermatol 1994;102:543. 9. Hall W, Liu C, Schneewind O, et al. Deleted HTLV-I provims in blood and cutaneous lesions of patients with mycosis fungoides. Science 1991;253:317-20. 10. Nagatani T, Matsuzaki T, Iemoto G, et al. Comparative study of cutaneous T cell lymphoma and adult T cell leukemia lymphoma. Cancer 1990;66:2380-6. 11. Pancake B, Zucker-Franklin D, Coutavas E. The cutaneous T cell lymphoma, mycosis fungoides, is a human T cell lymphotropic vires-associated disease. J Clin Invest 1995;95:547-54. 12. Whittaker S, Ng Y, Rustin M, et al. HTLV-I-associated cutaneous disease: a clinicopathological and molecular study of patients from the U.K. Br J Dermatol 1993; 128:483-92. 13. Detmar M, Panli G, Anagnostopoulos I, et al. A case of classical mycosis fungoides associated with human T-cell lymphotropic virus type I. Br J Dermatol 1991;124:198202. 14. Kawano F, Yamaguchi K, Nishimura H, et al. Variation in the clinical courses of adult T cell leukemia. Cancer 1985; 55:851-6.