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Regression of CD8+ pseudolymphoma after HIV antiviral triple therapy
J AM ACAD DERMATOL VOLUME 49, NUMBER 1
Case reports 139
Regression of CD8ⴙ pseudolymphoma after HIV antiviral triple therapy Noe¨l Emile Ce´lestin Schartz, MD,a Arnaud De La Blanchardie´re, MD,b Siham Alaoui, MD,a Patrice Morel, MD,a Franc¸ois Sigaux, MD, PhD,c Marie-Dominique Vignon-Pennamen, MD,d Be´atrice Flageul, MD,a and Ce´leste Lebbe´, MD, PhDa Paris, France To our knowledge, we report the first case of improvement of HIV-associated cutaneous CD8⫹ pseudolymphoma with highly active antiretroviral therapy. This favors the hypothesis of a reactive cutaneous infiltration by HIV-specific cytotoxic T cells in this disease. (J Am Acad Dermatol 2003;49:139-41.)
bout 20 cases of cutaneous CD8⫹ pseudolymphoma in HIV-infected patients1,2 have been reported in the medical literature. Extensive plaques or erythroderma that may be clinically reminiscent of a cutaneous T-cell lymphoma (mycosis fungoides or Se´ zary syndrome) are characteristic of this chronic skin disorder. It is frequently associated with eosinophilia. Histology shows a massive dermal infiltration of activated CD8⫹ T lymphocytes, with occasional epidermal tropism. So far, molecular genetic studies have not identified a clonal rearrangement of T-cell receptor genes.3 Before highly active antiretroviral therapy (HAART) was available, systemic corticosteroids were the standard treatment of this condition. Our case is original in its clinical manifestations and, to our knowledge, is the first reported case of improvement of HIV-associated cutaneous CD8⫹ pseudolymphoma with HAART.
A
CASE REPORT In March 1996, a 50-year-old heterosexual, HIVpositive, Senegalese man was admitted to the Department of Dermatology with itchy, erythematous skin lesions. He had been diagnosed with HIV infection 5 years earlier after an episode of tuberculosis (pleura and lymph node) when his CD4 cell count was 146 cells/mm3. From the Departments of Dermatology,a Infectious and Tropical diseases,b Hematology,c and Anatomopathology,d Hoˆpital SaintLouis AP-HP. Reprint requests: Ce´leste Lebbe, MD, PhD, Hoˆpital Saint Louis, 1, avenue Claude Vellefaux, F-75475 Paris Cedex 10, France. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.299
Fig 1. Vitiligoid hypopigmentation of the trunk after a 6-month evolution of erythroderma.
He had erythematous, scaly, scarcely infiltrated, confluent, sometimes crusty and excoriated plaques on his upper and lower limbs and on his face. They evolved in less than 6 months into a scattered, vitiligoid hypopigmentation of the trunk, arms, and thighs, while his face and the extremities of his limbs remained erythematous, scaly, and lichenoid (Fig 1). Hyperkeratosis of his palms and soles was observed, although his nails were unaffected. He had neither lymphadenopathy nor hepatosplenomegaly. Multiple skin biopsy specimens showed a lymphocytic infiltrate in the papillary dermis by medium-sized and large pleomorphic cells with mild epidermal tropism. Immunophenotyping studies (immunohistochemistry on frozen sections) revealed T lymphocytes expressing pan-T markers (CD2, CD3, CD5, CD7) and CD8 (Fig 2) but not CD25, HLA-DR, and CD30. There was no evidence of T-cell receptor–␥ chain or of immunoglobulin heavy chain gene rearrangement using polymerase
140 Case reports
Fig 2. A dense subepidermal bandlike T-cell infiltrate expressing CD8⫹. (Original magnification ⫻250.)
J AM ACAD DERMATOL JULY 2003
and lamivudine was started, then switched 6 weeks later to a triple combination regimen including a protease inhibitor (lamivudine, stavudine, and indinavir). In December 1996, a dramatic improvement was observed; the itchy and erythematous cutaneous lesions disappeared, leaving persistent lichenoid papules on the back of the hands. The plasma HIV viral load had fallen to 3800 copies/mL and the CD4 T-cell count had increased to 47 cells/mm3. The patient’s trunk, arms, and thighs also slowly regained their normal pigment (Fig 3). The dose of topical corticosteroids was tapered off. Histopathologic examination of the remaining lichenoid lesions of the hands showed a granulomatous infiltration of the papillary dermis consisting of a mixture of CD68⫹ macrophages (25% of the infiltrate) and CD2⫹, CD3⫹, CD5⫹, CD7⫹, CD25⫺, HLA-DR⫺, CD30⫺ T lymphocytes (50%-75% of the infiltrate). Although the CD4/CD8 ratio remained less than 1, the presence of CD4⫹ T cells (25%-50%) in the infiltrate contrasted with the findings of the initial biopsy (⬍10%). The patient died a few days later of status epilepticus.
DISCUSSION
Fig 3. Partial repigmentation after 1 month of HIV antiviral triple therapy.
chain reaction-based methods. Direct immunofluorescence was negative. Blood cell count showed 13 CD4⫹ T cells/mm3, 1075 CD8⫹ T cells/mm3, and 1000 eosinophils/mm3. There were no circulating Se´ zary cells and HTLV-1 and 2 serologies were negative. Plasma HIV viral load was estimated at 53,000 copies/mL. Differential diagnosis ruled out scabies, fungal infections, secondary syphilis, leprosy, lichen planus, drug-induced eruption, and toxic shock syndrome. The use of topical corticosteroids (betamethasone 17-valerate twice a day) for 1 month was unsuccessful. In October 1996, dual therapy with zidovudine
The diagnostic features of HIV-associated CD8⫹ pseudolymphoma are extensive erythematous mycosis fungoides-like plaques, eosinophilia, and a dermal CD8⫹ T-lymphocyte infiltrate without clonal T-cell receptor gene rearrangement. The clinical features of the erythroderma in our patient are original. They evolved into large patches of depigmentation over a 6-month period and disappeared rapidly with HAART. Cases reported previously were generally resistant to any kind of local or general treatment except systemic corticosteroids,2 whereas our patient responded to a triple combination (lamivudine, stavudine, and one protease inhibitor) of HIV-antiviral drugs. This can be compared with the dramatic reduction in the incidence of opportunistic infections and AIDS-related Kaposi’s sarcoma noticed since the use of HAART. By contrast, the consequences of HAART on AIDS-related lymphoma and other AIDS-related malignant conditions are insignificant or hardly noticeable.4-7 The residual lichenoid lesions of the hands are another interesting feature of our case. Histopathology showed granulomatous infiltration of the papillary dermis. Comparable granulomatous lesions histologically mimicking granuloma annulare have been reported at sites of resolved varicella-zoster virus reactivation infections. Granulomatous reactions in old zoster scars seem to be related to an immune reaction directed at persisting viral enve-
Case reports 141
J AM ACAD DERMATOL VOLUME 49, NUMBER 1
lope glycoproteins.8 Similarly, our patient’s lichenoid skin lesions could be related to an immune response to a persisting HIV antigen. In other respects, these lesions could be a manifestation of the immune restoration syndrome that is well described with HAART. The depletion of helper T lymphocytes with HIV infection often leads to poor or absent granuloma formation (eg, in sarcoidosis). In a recent case report, activation of the cell-mediated immune system with HAART was accompanied by new sarcoid granuloma formation.9 The pathogenesis of cutaneous CD8⫹ pseudolymphoma is not completely understood. The absence of a CD4⫹ helper T phenotype and the polyclonal proliferation of lymphocytes are arguments against cutaneous T-cell lymphoma. Bachelez et al10 and Bachelez, Hadida, and Gorochov11 demonstrated that CD8⫹ cytotoxic T lymphocyte lines isolated from the skin lesions exhibited a specific cytotoxic activity against HIV-1 gag- and pol- (in one patient) or env- (in one patient) expressing target cells. This study favors the hypothesis of a reactive cutaneous infiltration by HIV-specific cytotoxic T cells. In our case, the response to HAART and, to a lesser extent, the presence of residual lichenoid lesions are further indirect arguments for a reactive HIV-specific cytotoxic T-cell infiltrate and against an epidermotropic or pleomorphic lymphoma.
2.
3.
4.
5.
6.
7.
8.
9.
10.
We thank W. Whiteley for his assistance in manuscript preparation. REFERENCES 1. Zhang P, Chiriboga L, Jacobson M, Marsh E, Hennessey P, Schinella R, et al. Mycosis fungoides-like T cell cutaneous lym-
11.
phoid infiltrates in patients with HIV infection. Am J Dermatopathol 1995;17:29-35. Picard-Dahan C, Le Guyadec T, Grossin M, Fenton N, Raphael M, Simonpoli AM, et al. Erythrodermies pigmente´es au cours du SIDA. Ann Dermatol Venereol 1996;123:307-13. Guitart J, Variakojis D, Kuzel T, Rosen S. Cutaneous CD8⫹ T-cell infiltrates in advanced HIV infection. J Am Acad Dermatol 1999; 41:722-7. Brodt HR, Kamps BS, Gute P, Knupp B, Staszewski S, Helm EB. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997;11:1731-8. Jones JL, Hanson DL, Dworkin MS, Ward JW, Jaffe HW, the Adult/ Adolescent Spectrum of HIV Disease Project Group. Effect of antiretroviral therapy on recent trends in selected cancers among HIV-infected persons. J Acquir Immune Defic Syndr 1999;21:S11-7. Buchbinder SP, Holmberg SD, Scheer S, Colfax G, O’Malley P, Vittinghoff E. Combination antiretroviral therapy and incidence of AIDS-related malignancies. J Acquir Immune Defic Syndr 1999;21:S23-6. Rabkin CS, Testa MA, Huang J, Van Roenn JH. Kaposi’s sarcoma and non-Hodgkin’s lymphoma incidence trends in AIDS clinical trial group study participants. J Acquire Immune Defic Syndr 1999;21: S31-3. Nikkels AE, Pierard GE. Are granulomatous reactions in old zoster lesions due to an immune response to varicella-zoster virus envelope glucoproteins? Clin Exp Dermatol 1998;23:230-40. Mirmirani P, Maurer TA, Herndier B, McGrath M, Weinstein MD, Berger TG. Sarcoidosis in a patient with AIDS: a manifestation of immune restoration syndrome. J Am Acad Dermatol 1999;41: 285-6. Bachelez H, Hadida F, Parizot C, Flageul B, Kemula M, Dubertret L, et al. Oligoclonal expansion of HIV-specific cytotoxic CD8 T lymphocytes in the skin of HIV-1 infected patients with cutaneous pseudolymphoma. J Clin Invest 1998;101:2506-16. Bachelez H, Hadida F, Gorochov G. Massive infiltration of the skin by HIV specific cytotoxic CD8⫹ cells. N Engl J Med 1996;335: 61-2.
Case reports 139
Regression of CD8ⴙ pseudolymphoma after HIV antiviral triple therapy Noe¨l Emile Ce´lestin Schartz, MD,a Arnaud De La Blanchardie´re, MD,b Siham Alaoui, MD,a Patrice Morel, MD,a Franc¸ois Sigaux, MD, PhD,c Marie-Dominique Vignon-Pennamen, MD,d Be´atrice Flageul, MD,a and Ce´leste Lebbe´, MD, PhDa Paris, France To our knowledge, we report the first case of improvement of HIV-associated cutaneous CD8⫹ pseudolymphoma with highly active antiretroviral therapy. This favors the hypothesis of a reactive cutaneous infiltration by HIV-specific cytotoxic T cells in this disease. (J Am Acad Dermatol 2003;49:139-41.)
bout 20 cases of cutaneous CD8⫹ pseudolymphoma in HIV-infected patients1,2 have been reported in the medical literature. Extensive plaques or erythroderma that may be clinically reminiscent of a cutaneous T-cell lymphoma (mycosis fungoides or Se´ zary syndrome) are characteristic of this chronic skin disorder. It is frequently associated with eosinophilia. Histology shows a massive dermal infiltration of activated CD8⫹ T lymphocytes, with occasional epidermal tropism. So far, molecular genetic studies have not identified a clonal rearrangement of T-cell receptor genes.3 Before highly active antiretroviral therapy (HAART) was available, systemic corticosteroids were the standard treatment of this condition. Our case is original in its clinical manifestations and, to our knowledge, is the first reported case of improvement of HIV-associated cutaneous CD8⫹ pseudolymphoma with HAART.
A
CASE REPORT In March 1996, a 50-year-old heterosexual, HIVpositive, Senegalese man was admitted to the Department of Dermatology with itchy, erythematous skin lesions. He had been diagnosed with HIV infection 5 years earlier after an episode of tuberculosis (pleura and lymph node) when his CD4 cell count was 146 cells/mm3. From the Departments of Dermatology,a Infectious and Tropical diseases,b Hematology,c and Anatomopathology,d Hoˆpital SaintLouis AP-HP. Reprint requests: Ce´leste Lebbe, MD, PhD, Hoˆpital Saint Louis, 1, avenue Claude Vellefaux, F-75475 Paris Cedex 10, France. E-mail: [email protected]. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.299
Fig 1. Vitiligoid hypopigmentation of the trunk after a 6-month evolution of erythroderma.
He had erythematous, scaly, scarcely infiltrated, confluent, sometimes crusty and excoriated plaques on his upper and lower limbs and on his face. They evolved in less than 6 months into a scattered, vitiligoid hypopigmentation of the trunk, arms, and thighs, while his face and the extremities of his limbs remained erythematous, scaly, and lichenoid (Fig 1). Hyperkeratosis of his palms and soles was observed, although his nails were unaffected. He had neither lymphadenopathy nor hepatosplenomegaly. Multiple skin biopsy specimens showed a lymphocytic infiltrate in the papillary dermis by medium-sized and large pleomorphic cells with mild epidermal tropism. Immunophenotyping studies (immunohistochemistry on frozen sections) revealed T lymphocytes expressing pan-T markers (CD2, CD3, CD5, CD7) and CD8 (Fig 2) but not CD25, HLA-DR, and CD30. There was no evidence of T-cell receptor–␥ chain or of immunoglobulin heavy chain gene rearrangement using polymerase
140 Case reports
Fig 2. A dense subepidermal bandlike T-cell infiltrate expressing CD8⫹. (Original magnification ⫻250.)
J AM ACAD DERMATOL JULY 2003
and lamivudine was started, then switched 6 weeks later to a triple combination regimen including a protease inhibitor (lamivudine, stavudine, and indinavir). In December 1996, a dramatic improvement was observed; the itchy and erythematous cutaneous lesions disappeared, leaving persistent lichenoid papules on the back of the hands. The plasma HIV viral load had fallen to 3800 copies/mL and the CD4 T-cell count had increased to 47 cells/mm3. The patient’s trunk, arms, and thighs also slowly regained their normal pigment (Fig 3). The dose of topical corticosteroids was tapered off. Histopathologic examination of the remaining lichenoid lesions of the hands showed a granulomatous infiltration of the papillary dermis consisting of a mixture of CD68⫹ macrophages (25% of the infiltrate) and CD2⫹, CD3⫹, CD5⫹, CD7⫹, CD25⫺, HLA-DR⫺, CD30⫺ T lymphocytes (50%-75% of the infiltrate). Although the CD4/CD8 ratio remained less than 1, the presence of CD4⫹ T cells (25%-50%) in the infiltrate contrasted with the findings of the initial biopsy (⬍10%). The patient died a few days later of status epilepticus.
DISCUSSION
Fig 3. Partial repigmentation after 1 month of HIV antiviral triple therapy.
chain reaction-based methods. Direct immunofluorescence was negative. Blood cell count showed 13 CD4⫹ T cells/mm3, 1075 CD8⫹ T cells/mm3, and 1000 eosinophils/mm3. There were no circulating Se´ zary cells and HTLV-1 and 2 serologies were negative. Plasma HIV viral load was estimated at 53,000 copies/mL. Differential diagnosis ruled out scabies, fungal infections, secondary syphilis, leprosy, lichen planus, drug-induced eruption, and toxic shock syndrome. The use of topical corticosteroids (betamethasone 17-valerate twice a day) for 1 month was unsuccessful. In October 1996, dual therapy with zidovudine
The diagnostic features of HIV-associated CD8⫹ pseudolymphoma are extensive erythematous mycosis fungoides-like plaques, eosinophilia, and a dermal CD8⫹ T-lymphocyte infiltrate without clonal T-cell receptor gene rearrangement. The clinical features of the erythroderma in our patient are original. They evolved into large patches of depigmentation over a 6-month period and disappeared rapidly with HAART. Cases reported previously were generally resistant to any kind of local or general treatment except systemic corticosteroids,2 whereas our patient responded to a triple combination (lamivudine, stavudine, and one protease inhibitor) of HIV-antiviral drugs. This can be compared with the dramatic reduction in the incidence of opportunistic infections and AIDS-related Kaposi’s sarcoma noticed since the use of HAART. By contrast, the consequences of HAART on AIDS-related lymphoma and other AIDS-related malignant conditions are insignificant or hardly noticeable.4-7 The residual lichenoid lesions of the hands are another interesting feature of our case. Histopathology showed granulomatous infiltration of the papillary dermis. Comparable granulomatous lesions histologically mimicking granuloma annulare have been reported at sites of resolved varicella-zoster virus reactivation infections. Granulomatous reactions in old zoster scars seem to be related to an immune reaction directed at persisting viral enve-
Case reports 141
J AM ACAD DERMATOL VOLUME 49, NUMBER 1
lope glycoproteins.8 Similarly, our patient’s lichenoid skin lesions could be related to an immune response to a persisting HIV antigen. In other respects, these lesions could be a manifestation of the immune restoration syndrome that is well described with HAART. The depletion of helper T lymphocytes with HIV infection often leads to poor or absent granuloma formation (eg, in sarcoidosis). In a recent case report, activation of the cell-mediated immune system with HAART was accompanied by new sarcoid granuloma formation.9 The pathogenesis of cutaneous CD8⫹ pseudolymphoma is not completely understood. The absence of a CD4⫹ helper T phenotype and the polyclonal proliferation of lymphocytes are arguments against cutaneous T-cell lymphoma. Bachelez et al10 and Bachelez, Hadida, and Gorochov11 demonstrated that CD8⫹ cytotoxic T lymphocyte lines isolated from the skin lesions exhibited a specific cytotoxic activity against HIV-1 gag- and pol- (in one patient) or env- (in one patient) expressing target cells. This study favors the hypothesis of a reactive cutaneous infiltration by HIV-specific cytotoxic T cells. In our case, the response to HAART and, to a lesser extent, the presence of residual lichenoid lesions are further indirect arguments for a reactive HIV-specific cytotoxic T-cell infiltrate and against an epidermotropic or pleomorphic lymphoma.
2.
3.
4.
5.
6.
7.
8.
9.
10.
We thank W. Whiteley for his assistance in manuscript preparation. REFERENCES 1. Zhang P, Chiriboga L, Jacobson M, Marsh E, Hennessey P, Schinella R, et al. Mycosis fungoides-like T cell cutaneous lym-
11.
phoid infiltrates in patients with HIV infection. Am J Dermatopathol 1995;17:29-35. Picard-Dahan C, Le Guyadec T, Grossin M, Fenton N, Raphael M, Simonpoli AM, et al. Erythrodermies pigmente´es au cours du SIDA. Ann Dermatol Venereol 1996;123:307-13. Guitart J, Variakojis D, Kuzel T, Rosen S. Cutaneous CD8⫹ T-cell infiltrates in advanced HIV infection. J Am Acad Dermatol 1999; 41:722-7. Brodt HR, Kamps BS, Gute P, Knupp B, Staszewski S, Helm EB. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997;11:1731-8. Jones JL, Hanson DL, Dworkin MS, Ward JW, Jaffe HW, the Adult/ Adolescent Spectrum of HIV Disease Project Group. Effect of antiretroviral therapy on recent trends in selected cancers among HIV-infected persons. J Acquir Immune Defic Syndr 1999;21:S11-7. Buchbinder SP, Holmberg SD, Scheer S, Colfax G, O’Malley P, Vittinghoff E. Combination antiretroviral therapy and incidence of AIDS-related malignancies. J Acquir Immune Defic Syndr 1999;21:S23-6. Rabkin CS, Testa MA, Huang J, Van Roenn JH. Kaposi’s sarcoma and non-Hodgkin’s lymphoma incidence trends in AIDS clinical trial group study participants. J Acquire Immune Defic Syndr 1999;21: S31-3. Nikkels AE, Pierard GE. Are granulomatous reactions in old zoster lesions due to an immune response to varicella-zoster virus envelope glucoproteins? Clin Exp Dermatol 1998;23:230-40. Mirmirani P, Maurer TA, Herndier B, McGrath M, Weinstein MD, Berger TG. Sarcoidosis in a patient with AIDS: a manifestation of immune restoration syndrome. J Am Acad Dermatol 1999;41: 285-6. Bachelez H, Hadida F, Parizot C, Flageul B, Kemula M, Dubertret L, et al. Oligoclonal expansion of HIV-specific cytotoxic CD8 T lymphocytes in the skin of HIV-1 infected patients with cutaneous pseudolymphoma. J Clin Invest 1998;101:2506-16. Bachelez H, Hadida F, Gorochov G. Massive infiltration of the skin by HIV specific cytotoxic CD8⫹ cells. N Engl J Med 1996;335: 61-2.