Case 3 -

CD8+ Lymphoproliferative disorder in an HIV+ patient (Pseudo-mycosis fungoides in HIV) Jennifer M. McNiff Yale University School of Medicine New Haven, CT

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Clinical History 40 year old female who presented with erythroderma after years of atopic dermatitis. Important underlying history (initially withheld) is that she is HIV+ and has very low CD4 counts Case 3 - Figure 1 - At low power, there is a band-like lymphocytic infiltrate with psoriasiform epidermal hyperplasia and dermal fibrosis. Case 3 - Figure 2 - There is minimal epidermal spongiosis, with dry parakeratosis. The papillary dermal collagen shows wiry fibrosis, and the infiltrate is relatively dense. Case 3 - Figure 3 - Note the presence of intraepidermal lymphocytes in the absence of spongiosis, forming small Pautrier microabscesses. Some of the lymphocytes are enlarged with irregular nuclear contours. Case 3 - Figure 4 - Scattered intraepidermal collections of lymphocytes are identified in association with irregular psoriasiform epidermal hyperplasia and hyperkeratosis without spongiosis. It is well known that patients infected with HIV may develop lymphoma. In most cases, these are high-grade extranodal B-cell lymphomas. There are some reports of rashes in HIV positive patients that clinically and histologically resemble mycosis fungoides (MF). In a subset of cases studied immunophenotypically, however, the infiltrates are composed of a predominance of CD8-positive cells, rather than CD4-positive cells that typify MF. Molecular studies to date have shown no evidence of clonality of infiltrating lymphocytes. Such rashes are typically associated with profound lymphopenia, advanced HIV infection, and a poor outcome. In this setting, the cutaneous infiltrates have been interpreted as a unique response to a high viral load. Regression of cutaneous lesions occurs after combined retroviral therapy. The histologic features can be difficult to differentiate from true mycosis fungoides and include: Papillary and mid-dermal lymphocytic infiltrates Epidermotropism and Pautrier-like microabscesses Wiry papillary dermal fibrosis Parakeratosis and hyperkeratosis Eosinophils may be seen Predominance of CD8-positive lymphocytes The differential diagnosis mainly revolves around the possibility of mycosis fungoides/Sézary syndrome. Patients are often erythrodermic, and biopsies of erythroderma are frequently difficult to diagnose, regardless of the etiology of erythroderma. Other causes of erythroderma may also be considered in this setting, including eczematous dermatitis, reaction to medication, and atypical pityriasis rubra pilaris.    The proposed explanation for these cutaneous infiltrates in advanced HIV infection likely relates to a specific CD8+ response to HIV viral proteins. It has been shown that in patients infected by HIV, proteins from this virus are expressed in Langerhans cells in the epidermis. Langerhans cells could play a role in presenting HIV antigens to lymphocytes. Furthermore, functional studies with CD8+ T-cells collected from skin infiltrates of these patients have shown a specific cytotoxic immune response to HIV protein products. During advanced disease, when CD4 counts are low, there is typically a rise in viral load. Theoretically, increased numbers of viral particles in the Langerhans cells of the epidermis may trigger a specific reactive host inflammatory response in the form of CD8-positive lymphocytes infiltrating the epidermis and superficial dermis. Presumably, early in the course of HIV infection, CD8+ cytotoxic cells play a role in lysing infected cells and controlling disease. However, as the viral load increases, CD8+ cytotoxic response may go unchecked and mimic a neoplastic process such as cutaneous T cell lymphoma. The biologic significance of these cutaneous lymphoid infiltrates in advanced HIV infection is difficult to assess, because patients often have a greatly shortened lifespan due to advanced immunodeficiency. In one study by Guitart et al, 8 of 9 patients with cutaneous CD8+ T cell infiltrates in advanced HIV infection died within one year of diagnosis, precluding follow-up of the evolution of the cutaneous lesions. However, there are recent reports of regression of so-called CD8-positive pseudolymphoma in this setting, after HIV antiviral triple therapy. This observation supports the hypothesis that these infiltrates represent a reactive phenomenon triggered increasing numbers of viral particles in the skin, with the potential to resolve if the viral load decreases. References Burns MK, Cooper KD. Cutaneous T-cell lymphoma associated with HIV infection. J Am Acad Dermatol 29:394-9, 1993. Zhang P et al. Mycosis fungoides-like T-cell cutaneous lymphoid infiltrates in patients with HIV infection. Am J Dermatopathol 1995;17:29-35. Guitart J et al. Cutaneous CD8+ T cell infiltrates in advanced HIV infection. J Am Acad Dermatol 1999 ;41:722-727. Henry M et al. Epidermal Langerhans cells of AIDS patients express HIV-1 regulatory and structural genes. J Invest Dermatol 1994;103:593-596. Bachelez H 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;101:2506-2516. Schartz NEC et al. Regression of CD8+ pseudolymphoma after HIV antiviral triple therapy. J Am Acad Dermatol 2003;49:139-41. Gachelez H, Hadida F, Gorochov G. Massive infiltration of the skin by HIV-specific cytotoxic CD8+ T cells. N Eng J Med 1996 ;335:61-62.