Dermatology Online Journal

Rapid clinical change in lesions of atypical cutaneous lymphoproliferative disorder in an HIV patient: A case report and review of the literature
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

1. University of Michigan, Ann Arbor, Michigan. regbers@med.umich.edu
2. NGI/Dianon Laboratories, Los Angeles, California

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Abstract

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.

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Introduction

HIV associated atypical cutaneous lymphoproliferative disorder (ACLD), is a rare complication of HIV infection. Since first described in 1989 by Longacre et al [1] and Janier et al [2], 46 cases have been reported [1-10]. Other descriptions used for this condition include HIV associated cutaneous CD8+ pseudolymphoma [6, 10], pseudo-Sézary syndrome [2], and Mycosis Fungoides-like lesions [3]. 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).

Case

Figure 1	Figure 2
Figure 1. Clinical appearance at presentation and at follow-up, after 2 weeks of antiretroviral therapy: A – B, face and hands at presentation. Generalized papular eruption, some targetoid papules with a dusky center (green arrows). C – D, face, hands and feet at 2-week follow-up. Desquamating hyperpigmented patches and plaques on the face, with small discrete hyperpigmented papules and patches on the palms and soles. Figure 2. Moderately dense perivascular and interstitial infiltrate of small lymphocytes and intermediate-sized lymphoid cells with irregular nuclear contours that express CD8. Focal areas of infiltration of overlying epidermis (yellow arrows) with occasional collections of atypical lymphoid cells in the epidermis (red arrows). (A, Hematoxylin-eosin stain, original magnification: x100, inset original magnification: x400; B, CD8 immunostain, original magnification: x40, inset original magnification: x400.)

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.

Discussion

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 [11]. 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 [15]. Photoeruptions [16] and drug eruptions [17] 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 [20]. 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 [21]. 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 [22]. The only fully characterized case reports of ATLL with CD4-CD8+ infiltrate in HTLV-I [23] and HTLV-II [24] 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 [25]. 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 [8], 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 [26]. 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%) [7]. Although differences exist, the clinical and histological findings are not specific for ACLD and typically require additional diagnostic testing [27].

Immunophenotyping and T-cell receptor (TCR) rearrangement analysis may help to distinguish pseudolymphomas from CTCL in patients without HIV [28]. 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 [28]. 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 [6]. Considering HIV mRNA has been demonstrated in epidermal Langerhans cells [30], 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 [31] 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 [32]. Importantly, the activity of the CD8+ T-cell subset decreases with effective anti-retroviral treatment [33]. 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 [5] and partial remission was observed in one case by Bachelez et al [4]. The latter group has also reported substantial improvement in the rash with dual antiviral therapy, further substantiated by Schartz et al, [10] 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 [33], because antiretroviral therapy induces a quick decrease in viral load and increase in CD4+ T-cell counts [34], with subsequent changes in CD8+ T-cell receptor repertoire [35]. 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.

Conclusion

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.

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