Rapid clinical change in lesions of atypical cutaneous lymphoproliferative disorder in an HIV patient: A case report and review of the literature
- Author(s): Egbers, Robert;
- Egbers, Robert George;
- Do, Thy Thy;
- Su, Lyndon;
- Helfrich, Yolanda R;
- Gudjonsson, Johann E
- et al.
Published Web Locationhttps://doi.org/10.5070/D38tt2b1rc
Rapid clinical change in lesions of atypical cutaneous lymphoproliferative disorder in an HIV patient: A case report and review
of the literature1. University of Michigan, Ann Arbor, Michigan. firstname.lastname@example.org
Robert George Egbers MD MS1, Thy Thy Do MBBS1, Lyndon Su MD2, Yolanda R Helfrich MD1, Johann E Gudjonsson MD PhD1
Dermatology Online Journal 17 (9): 4
2. NGI/Dianon Laboratories, Los Angeles, California
BACKGROUND: HIV associated atypical cutaneous lymphoproliferative disorder (ACLD) is a rare condition characterized by a pruritic, often generalized, eruption of patches and plaques or erythroderma clinically simulating mycosis fungoides (MF) or Sézary syndrome. A polyclonal CD8+ T-cell infiltrate on biopsy can help differentiate ACLD from MF or Sézary syndrome, but the clinical and histopathologic appearance must also be considered. Accurate diagnosis is imperative because HAART therapy has been reported to improve this condition in some patients. OBSERVATION: We report a case of HIV associated ACLD, with an atypical presentation, initially consisting of diffuse papules, some with a dusky targetoid center. Two weeks after starting antiviral therapy the papules flattened, evolving to xerotic, hyperpigmented macules. CONCLUSION: The working-theory of a reactive etiology for this condition might explain the evolution in appearance following initiation of HAART. The presence of papules with a dusky targetoid center suggests that this condition should be considered in the differential diagnosis with syphilis or atypical erythema multiforme in HIV patients.
HIV associated atypical cutaneous lymphoproliferative disorder (ACLD), is a rare complication of HIV infection. Since first described in 1989 by Longacre et al  and Janier et al , 46 cases have been reported [1-10]. Other descriptions used for this condition include HIV associated cutaneous CD8+ pseudolymphoma [6, 10], pseudo-Sézary syndrome , and Mycosis Fungoides-like lesions . It typically presents with MF-like lesions or erythroderma; however, we report a case with diffuse papules, some with an atypical dusky targetoid center, with a rapid clinical evolution following highly active anti-retroviral therapy (HAART).
A 51-year-old HIV+ man was referred with a diffuse, mildly pruritic papular eruption. The patient also had a history of hepatitis C and recurrent secondary syphilis. He first noticed a rash during hospitalization for Pneumocystis jiroveci (carinii) pneumonia and Cryptococcal meningitis two months prior. Fatigue was noted on review of systems, but he had no fever, chills, or other symptoms. He was not on antiretroviral therapy, but was taking fluconazole and trimethoprim-sulfamethoxazole prophylaxis. On examination, multiple papules, some with a dusky targetoid center, were present on the face, nasal mucosa, upper neck, shoulders and extremities. Oral mucosa, hands and feet were without visible lesions. Axillary nodes were enlarged, but no hepatosplenomegaly was noted.
Skin biopsy demonstrated a perivascular and interstitial infiltrate of small lymphocytes, intermediate lymphoid cells with irregular nuclear contours, and few histiocytes and eosinophils on hematoxylin and eosin stain. Focal infiltration of the epidermis, with mild spongiosis, and rare apoptotic keratinocytes were also observed. Immunostaining showed predominantly CD8+ lymphoid cells, with scattered CD4+ lymphoid cells, CD68+ histiocytes, few CD30+ large cells, and rare CD20+ B-cells. Gomori methenamine silver (GMS), Fite, and Steiner silver stains were negative for fungi, mycobacteria, and spirochetes. EBV was not detected by in-situ hybridization. Additional deeper sections through the tissue block failed to disclose molluscum bodies. T-cell receptor gene rearrangement was negative by polymerase chain reaction. Deep tissue, acid-fast bacilli and fungal cultures and smears demonstrated no organisms. Screening for syphilis and Cryptococcus was negative by rapid plasma reagin and by Cryptococcus antigen respectively. At the time of presentation, his CD4+ count was 71 cells/mm³, CD8+ count was 3,951 cells/mm³, and an HIV viral load was 43,700 copies/mL.
|Figure 1||Figure 3|
|Figure 3. A close-up of the patient’s leg at week 2 showing hyperpigmented patches and plaques with xerosis.|
Treatment with HAART was initiated, which included abacavir, lamivudine, lopinavir, and ritonavir. At follow-up two weeks after starting HAART, the eruption had dramatically changed in appearance to large desquamating patches and hyperpigmented plaques on the face, trunk, and extremities, suggestive of post-inflammatory changes. Small discrete hyperpigmented papules and patches also had appeared on the palms and soles. Unfortunately, the patient succumbed to an unrelated infectious complication of his HIV two months later, but in the interim the skin rash had continued to improve while on HAART.
Rarely, cutaneous eruptions have been reported in HIV patients with a clinical appearance similar to that of MF. A CD8+ T-cell predominant infiltrate on biopsy without evidence of clonal expansion is characteristic of this condition, termed atypical cutaneous lymphoproliferative disorder (ACLD). We report a case of ACLD with a previously unreported presentation of generalized papules, some with a dusky targetoid center.
This initial clinical presentation was concerning for atypical erythema multiforme (EM) or secondary syphilis . Both conditions occur more frequently in HIV patients [12-14], but neither were consistent with the case described here. Secondary syphilis was ruled out; both serum RPR and Steiner silver staining of biopsy sections were negative . Photoeruptions  and drug eruptions  are also observed with increased frequency in HIV positive individuals, but the histological and/or clinical features were not suggestive of these in our patient. Osborne et al have extensively reviewed the approach to other HIV related cutaneous conditions [18, 19].
Secondary cutaneous spread of lymphoma is sometimes included in the differential diagnosis, but the primary site is usually identified prior to cutaneous spread . Although the clinical morphology of our case has not been previously reported in HIV associated ACLD, similar lesions have been described in cutaneous adult T-cell lymphoma/leukemia . Adult T-cell leukemia/lymphoma (ATLL) is associated with human T-cell lymphotropic virus types 1 and possibly 2 (HTLV-1 and HTLV-2). A CD4-CD8+ T-cell infiltrate, without clonal TCR rearrangement, as described in our case has not been reported in the literature for HTLV associated ATLL patients. Thus, the vast majority of ATLL are CD4+CD8-, and only rarely CD4+CD8+ double positive . The only fully characterized case reports of ATLL with CD4-CD8+ infiltrate in HTLV-I  and HTLV-II  had just one patient each and both were monoclonal [23, 24]. The tendency towards a CD4+CD8- immunophenotype likely relates to the susceptibility of CD4+ lymphocytes to undergo transformation following HTLV infection . Therefore, the CD8+ nature of the infiltrate along with the lack of clonality in this case makes the diagnosis of ATLL extremely unlikely.
The clinical and histological appearance of ACLD, which was summarized by Friedler et al , can be difficult to differentiate from MF. However, there are some differences that can help with the diagnosis. As seen in our case, the distribution of the eruption is typically generalized at presentation (76%) [1-3, 5-8, 10]; the remainders tend to be photodistributed (17%) [7, 8] rather than in sun protected sites (7%) [3, 8, 9], in contrast to patch or plaque stage MF . Cytologic atypia is commonly observed in ACLD biopsies,and epidermotropism is reported in less than half of the cases (37%) and is typically mild [7, 8, 9]. Epidermal lymphocyte collections, such as Pautrier microabscesses, occur rarely (10%) . Although differences exist, the clinical and histological findings are not specific for ACLD and typically require additional diagnostic testing .
Immunophenotyping and T-cell receptor (TCR) rearrangement analysis may help to distinguish pseudolymphomas from CTCL in patients without HIV . Unlike the picture in MF, all 39 cases of HIV associated ACLD with reported immunostaining showed a predominant CD8+ phenotype. Whereas depletion of T-cell maturity markers CD2, CD3, CD5, and CD7 can occur even in early MF, this is not a common feature of ACLD . Although TCR clonality is somewhat sensitive for MF samples (60-90%) [28, 29], it was not found in any of the 13 ACLD cases tested by PCR [2, 3, 4, 6, 7, 9, 10]. Thus, positive clonal rearrangement on TCR analysis or aberrant immunophenotype would support a diagnosis of lymphoma rather than ACLD in HIV patients.
Very rarely did reviewed cases eventually progress to frank lymphoma (4.2%), supporting the notion that the observed clinicopathologic manifestations more likely represent a unique disease, rather than an early lymphoma. The pathogenesis of HIV associated ACLD is not completely characterized, but like pseudolymphomas, it is considered reactive rather than malignant. Infiltrating CD8+ T-cells isolated from ACLD patients have shown MHC-1 dependant cytotoxic activity against cells expressing HIV-1 viral gag, pol, and env proteins . Considering HIV mRNA has been demonstrated in epidermal Langerhans cells , the CD8+ T-cell infiltrate of ACLD may be exhibiting a reaction to HIV antigens and infected cells in the skin. In addition, increased activity of CD8+ T-cell populations has been observed in HIV patients  and may relate to depletion of CD4+ regulatory T-cells, which is associated with at least a 10-fold expansion of the CD8+ T-cell population . Importantly, the activity of the CD8+ T-cell subset decreases with effective anti-retroviral treatment . Therefore, the CD8+ T-cell infiltrate in ACLD may relate to unrestricted activity of the CD8+ T-cells as a reaction to depletion of CD4+ regulatory cells, increased levels of HIV antigens, and increased numbers of infected cells in the skin. (Table 1)
Treatment of HIV associated ACLD has proven to be arguably more challenging than diagnosis. Only, marginal success with topical steroids, ultraviolet, retinoids, or chemotherapeutic therapies has been reported. Resolution of ACLD has been reported with systemic corticosteroid therapy in two cases by Picard-Dahan et al  and partial remission was observed in one case by Bachelez et al . The latter group has also reported substantial improvement in the rash with dual antiviral therapy, further substantiated by Schartz et al,  who reported “drastic” improvement in one case after initiation of highly active antiretroviral therapy (HAART). Despite a lack of prospective trials and a limited number of cases, HAART and possibly systemic corticosteroids should be considered as the main treatment options.
HIV associated ACLD is frequently reported to progress in severity with time. Typically, patients present in advanced HIV disease, with a low average CD4 count (98 CD4+ T-cells/mm³). Over half of the cases (52%) pass-away within one year after initial presentation [1, 2, 7, 8, 10] and most do not survive more than two years (81%) [5, 7, 8]. Although the cause of death is often secondary to other complications of AIDS, those patients with greater skin involvement, nodal involvement, or an erythrodermic presentation typically have a worse prognosis. It remains unclear if the development of ACLD directly alters the course of underlying HIV infection or if the high mortality relates to the significant immunosuppression commonly present at its onset.
It is conceivable that antiretroviral therapy could alter the course of ACLD as indicated by Gray et al , because antiretroviral therapy induces a quick decrease in viral load and increase in CD4+ T-cell counts , with subsequent changes in CD8+ T-cell receptor repertoire . As was observed in our case, the rapid change observed at follow-up may represent the first step towards resolution of the rash. The appearance of the lesions changed so drastically between the initial evaluation and 2 week follow-up, without complete resolution, that a clear initial assessment of improvement could not be made with certainty. The appearance after 2 weeks of antiretroviral therapy may have represented development of early post-inflammatory changes, which would be consistent with the working theory of pathophysiology and is consistant with results of previous HAART in ACLD. Improvement was reported over the subsequent 2 months, while HAART continued in our case.
This case highlights the variability in presentation and evolution of HIV associated ACLD. The working-theory of a reactive etiology for this condition might explain the rapid clinical change following initiation of HAART. A follow-up biopsy would have been informative in this setting to identify any significant differences in the infiltrate compared to that at presentation. The initial appearance, which included dusky targetoid papules in this case, suggests that ACLD in HIV patients is not limited to a classic MF-like appearance.
References1. Longacre TA, Foucar K, Koster F, Burgdorf W. Atypical cutaneous lymphoproliferative disorder resembling mycosis fungoides in AIDS. Report of a case with concurrent Kaposi's sarcoma. Am J Dermatopathol. 1989 Oct;11(5):451-6. [PubMed]
2. Janier M, Katlama C, Flageul B, Valensi F, Moulonguet I, Sigaux F, Dompmartin D, Civatte J. The pseudo-Sezary syndrome with CD8 phenotype in a patient with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1989 May 1;110(9):738-40. [PubMed]
3. Zhang P, Chiriboga L, Jacobson M, Marsh E, Hennessey P, Schinella R, Feiner H. Mycosis fungoideslike T-cell cutaneous lymphoid infiltrates in patients with HIV infection. Am J Dermatopathol. 1995 Feb;17(1):29-35. [PubMed]
4. Bachelez H, Hadida F, Gorochov G. Massive infiltration of the skin by HIV-specific cytotoxic CD8+ T cells. N Engl J Med. 1996 Jul 4;335(1):61-2. [PubMed]
5. Picard-Dahan C, Le Guyadec T, Grossin M, Feton N, Raphael M, Simonpoli AM, Crickx B, Belaich S. [Pigmented erythroderma in AIDS. 5 cases]. Ann Dermatol Venereol. 1996;123(5):307-13. [PubMed]
6. Bachelez H, Hadida F, Parizot C, Flageul B, Kemula M, Dubertret L, Debree P, Gorochov G. Oligoclonal expansion of HIV-specific cytotoxic CD8 T lymphocytes in the skin of HIV-1-infected patients with cutaneous pseudolymphoma. J Clin Invest. 1998 Jun 1;101(11):2506-16. [PubMed]
7. Guitart J, Variakojis D, Kuzel T, Rosen S. Cutaneous CD8 T cell infiltrates in advanced HIV infection. J Am Acad Dermatol. 1999 Nov;41(5 Pt 1):722-7. [PubMed]
8. Friedler S, Parisi MT, Waldo E, Wieczorek R, Sidhu G, Rico MJ. Atypical cutaneous lymphoproliferative disorder in patients with HIV infection. Int J Dermatol. 1999 Feb;38(2):111-8. [PubMed]
9. Pirovano S, Signorini L, Facchetti F, Santoro A, Albertin A, Imberti L. Polyclonal T-cell expansions in a HIV(+) patient with atypical cutaneous lymphoproliferative disorder, large granular lymphocyte proliferation and SENV infection. Haematologica. 2001 Aug;86(8):881-2. [PubMed]
10. Schartz NE, De La Blanchardiere A, Alaoui S, Morel P, Sigaux F, Vignon-Pennamen MD, Flageul B, Lebbe C. Regression of CD8+ pseudolymphoma after HIV antiviral triple therapy. J Am Acad Dermatol. 2003 Jul;49(1):139-41. [PubMed]
11. Hall CS, Klausner JD, Bolan GA. Managing Syphilis in the HIV-infected Patient. Curr Infect Dis Rep. 2004 Feb;6(1):72-81. [PubMed]
12. Buchacz K, Klausner JD, Kerndt PR, Shouse RL, Onorato I, McElroy PD, Schwendemann J, Tambe PB, Allen M, Coye F, Kent C, Park MN, Hawkins K, Samoff E, Brooks JT. HIV incidence among men diagnosed with early syphilis in Atlanta, San Francisco, and Los Angeles, 2004 to 2005. J Acquir Immune Defic Syndr. 2008 Feb 1;47(2):234-40. [PubMed]
13. Smith KJ, Skelton HG, Yeager J, Ledsky R, Ng TH, Wagner KF. Increased drug reactions in HIV-1-positive patients: a possible explanation based on patterns of immune dysregulation seen in HIV-1 disease. The Military Medical Consortium for the Advancement of Retroviral Research (MMCARR). Clin Exp Dermatol. 1997 May;22(3):118-23. [PubMed]
14. Coopman SA, Johnson RA, Platt R, Stern RS. Cutaneous disease and drug reactions in HIV infection. N Engl J Med. 1993 Jun 10;328(23):1670-4. [PubMed]
15. Kingston AA, Vujevich J, Shapiro M, Hivnor CM, Jukic DM, Junkins-Hopkins JM, Jih DM, Kostman JR, James WD. Seronegative secondary syphilis in 2 patients coinfected with human immunodeficiency virus. Arch Dermatol. 2005 Apr;141(4):431-3. [PubMed]
16. Berger TG, Dhar A. Lichenoid photoeruptions in human immunodeficiency virus infection. Arch Dermatol. 1994 May;130(5):609-13. [PubMed]
17. Fiszenson-Albala F, Auzerie V, Mahe E, Farinotti R, Durand-Stocco C, Crickx B, Descamps V. A 6-month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol. 2003 Nov;149(5):1018-22. [PubMed]
18. Osborne GE, Taylor C, Fuller LC. The management of HIV-related skin disease. Part I: infections. Int J STD AIDS. 2003 Feb;14(2):78-86; quiz 7-8. [PubMed]
19. Osborne GE, Taylor C, Fuller LC. The management of HIV-related skin disease. Part II: neoplasms and inflammatory disorders. Int J STD AIDS. 2003 Apr;14(4):235-40; quiz 41. [PubMed]
20. Penneys NS. Skin manifestations of AIDS. 2nd ed. London: M. Dunitz; 1995.
21. Ohtani T, Deguchi M, Aiba S. Erythema multiforme-like lesions associated with lesional infiltration of tumor cells occurring with adult T-cell lymphoma/leukemia. Int J Dermatol. 2008 Apr;47(4):390-2. [PubMed]
22. Ciminale V, Hatziyanni M, Felber BK, Bear J, Hatzakis A, Pavlakis GN. Unusual CD4+CD8+ phenotype in a greek patient diagnosed with adult T-cell leukemia positive for human T-cell leukemia virus type I (HTLV-I). Leuk Res. 2000 Apr;24(4):353-8. [PubMed]
23. Bittencourt AL, Barbosa HS, Requião C, da Silva AC, Vandamme AM, Van Weyenbergh J, Farré L. Adult T-cell leukemia/lymphoma with a mixed CD4+ and CD8+ phenotype and indolent course. J Clin Oncol. 2007 Jun 10;25(17):2480-2. [PubMed]
24. Poiesz B, Dube D, Dube S, Love J, Papsidero L, Uner A, Hutchinson R. HTLV-II-associated cutaneous T-cell lymphoma in a patient with HIV-1 infection. N Engl J Med. 2000 Mar 30;342(13):930-6. [PubMed]
25. Sibon D, Gabet AS, Zandecki M, Pinatel C, Thête J, Delfau-Larue MH, Rabaaoui S, Gessain A, Gout O, Jacobson S, Mortreux F, Wattel E. HTLV-1 propels untransformed CD4 lymphocytes into the cell cycle while protecting CD8 cells from death. J Clin Invest. 2006 Apr;116(4):974-83. [PubMed]
26. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, Ralfkiaer E, Chimenti S, Diaz-Perez JL, Duncan LM, Grange F, Harris NL, Kempf W, Kerl H, Kurrer M, Knobler R, Pimpinelli N, Sander C, Santucci M, Sterry W, Vermeer MH, Wechsler J, Whittaker S, Meijer CJ. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May 15;105(10):3768-85. [PubMed]
27. Bakels V, van Oostveen JW, van der Putte SC, Meijer CJ, Willemze R. Immunophenotyping and gene rearrangement analysis provide additional criteria to differentiate between cutaneous T-cell lymphomas and pseudo-T-cell lymphomas. Am J Pathol. 1997 Jun;150(6):1941-9. [PubMed]
28. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, Burg G, Cerroni L, Dreno B, Glusac E, Guitart J, Heald PW, Kempf W, Knobler R, Lessin S, Sander C, Smoller BS, Telang G, Whittaker S, Iwatsuki K, Obitz E, Takigawa M, Turner ML, Wood GS. Defining early mycosis fungoides. J Am Acad Dermatol. 2005 Dec;53(6):1053-63. [PubMed]
29. Ponti R, Fierro MT, Quaglino P, Lisa B, Paola FC, Michela O, Paolo F, Comessatti A, Novelli M, Bernengo MG. TCRgamma-chain gene rearrangement by PCR-based GeneScan: diagnostic accuracy improvement and clonal heterogeneity analysis in multiple cutaneous T-cell lymphoma samples. J Invest Dermatol. 2008 Apr;128(4):1030-8. [PubMed]
30. Henry M, Uthman A, Ballaun C, Stingl G, Tschachler E. Epidermal langerhans cells of AIDS patients express HIV-1 regulatory and structural genes. J Invest Dermatol. 1994 Oct;103(4):593-6. [PubMed]
31. Ribeiro RM, Mohri H, Ho DD, Perelson AS. In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: why are CD4+ but not CD8+ T cells depleted? Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15572-7. [PubMed]
32. Kursar M, Bonhagen K, Fensterle J, Kohler A, Hurwitz R, Kamradt T, Kaufmann SH, Mittrucker HW. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses. J Exp Med. 2002 Dec 16;196(12):1585-92. [PubMed]
33. Gray CM, Schapiro JM, Winters MA, Merigan TC. Changes in CD4+ and CD8+ T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience. AIDS Res Hum Retroviruses. 1998 May 1;14(7):561-9. [PubMed]
34. Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117-22. [PubMed]
35. Gorochov G, Neumann AU, Parizot C, Li T, Katlama C, Debre P. Down-regulation of CD8+ T-cell expansions in patients with human immunodeficiency virus infection receiving highly active combination therapy. Blood. 2001 Mar 15;97(6):1787-95. [PubMed]
© 2011 Dermatology Online Journal