World Journal of AIDS, 2013, 3, 10-15
http://dx.doi.org/10.4236/wja.2013.31002 Published Online March 2013 (http://www.scirp.org/journal/wja)
Atypical Cutaneous Lymphoproliferative Disorder: A
Fatal Mimic of Cutaneous T-Cell Lymphoma in a Patient
with HIV Infection
Veronica Nguyen1, Russell Dorer2, David M. Aboulafia3,4*
1Albany Medical College, Albany, USA; 2Division of Pathology, Virginia Ma son Medical Center, Seattle, USA; 3Division of Hema-
tology and Oncology, Virginia Mason Medical Center, Seattle, USA; 4Division of Hematology, University of Washington, Seattle,
USA.
Received November 14th, 2012; revised December 16th, 2012; accepted December 28th, 2012
ABSTRACT
Atypical cutaneous lymphoproliferative disorder (ACLD) is a rare condition that has been associated with HIV infec-
tion. Patients with ACLD present with diffuse, erythematous and pruritic skin lesions accompanied by generalized
lymphadenopathy. The clinical characteristics of ACLD overlap most notably with several other conditions including
Mycosis Fungoides/Sézary Syndrome (MF/SS), a cutaneous lymphoma of T-cell lineage. Unlike Mycosis Fungoides,
the noxious infiltrates of ACLD are not monoclonal but polyclonal and consist of cytotoxic CD8+ T-cells instead of
CD4+ T-cells or B-cells. Highly active antiretroviral therapy (HAART) has been reported to improve ACLD. We de-
scribe the case of a Caucasian man with longstanding HIV infection who presented with severe erythroderma. Skin and
lymph node biopsies sh owed polyclonal CD8+ T-cell infiltrates. Gene rearrangement studies did not reveal an obvious
clonal disorder. Hallmark peripheral blood findings consisting of a severe depletion of CD4+ T-lymphocytes and
markedly elevated CD8+ cells provided an important diagnostic clue. Despite the purported benefits of HAART in
ameliorating this disorder, erythroderma and extreme pruritus improved only after the patient began taking mycophe-
nolate mofetil and hydroxyurea. Unfortunately, he succumbed to complications of methicillin-resistant Staphylococcus
aureus septicemia. We alert readers to this rare HIV-associated condition which may mimic other benign and malignant
skin conditions and briefly discuss diagnostic and therapeu tic options.
Keywords: Atypical Cutaneous Lymphoproliferative Disorder; Mimic Fatal; Cutaneous T-Cell Lymphoma;
HIV Infe c t ion
1. Introduction
Atypical cutaneous lymphoproliferative disorder (ACLD)
is a rare but potentially life-threatening complication of
HIV infection. It most commonly manifests as diffuse
erythroderma due to massive infiltration of polyclonal
CD8+ T-cells involving the dermis and epidermis [1].
First described by Longacre and colleagues in 1989,
ACLD has been reported under a number of other pseu-
donyms including HIV-associated cutaneous CD8+
pseudolymphoma, p seudo -Sézary syndrome and Mycosis
Fungoides (MF)-like lesions [2,3]. When CD8+ poly-
clonal cells involve other organs, most commonly the
parotids, but also the lungs, liver, gastrointestinal tract
and kidneys, it is referred to as diffuse infiltrative lym-
phocytosis syndrome (DILS) [4]. When DILS is re-
stricted to the head and neck, it manifests as bilateral
parotid gland enlargement with Sicca syndrome and as-
sociated lymphadenopathy. The lung is the most com-
mon extraglandular site of DILS, and patients with pul-
monary involvement often present with fever, shortness
of breath and interstitial infiltrates which, in the absence
of appropriate immunostains from sputum or pulmonary
lavage, can be mistaken for Pneumocystis Jiroveci
pneumonia [5]. DILS can also present as a polyneuropa-
thy that can include both cervical and lumbosacral nerves
[6]. A tipoff that the patient may have ACLD or DILS is
peripheral blood lymphocyte flow cytometry abnormali-
ties showing depletion of CD4+ T-cells and a striking
increase in CD8+ T-cells in the setting of a normal or
increased total lymphocyte count [4].
Prior to the advent of HAART, symptoms of individu-
als with ACLD or DILS rarely improved [3,7]. Systemic
multiagent anti-lymphoma chemotherapy, antivirals, oral,
topical and systemic corticosteroids and oral ketocona-
*Corresponding a uthor.

Atypical Cutaneous Ly mphoproliferative Disorder: A Fatal Mimic of Cutaneous
T-Cell Lymphoma in a Patient with HIV Infec tion 11
zole have all been used in an attempt to treat this condi-
tion, but none of these strategies proved clearly success-
ful in the pre-HAART era [2,3]. More recently, small
case series and isolated case reports have suggested that
HAART significantly improves the erythroderma and
end-organ dysfunction associated with ACLD and that its
use has led to a decreased incidence of this condition
[2,7].
We describe a patient with HIV infection who pre-
sented with severe pruritus and diffuse erythroderma,
weight loss, and palpable and generalized lymphade-
nopathy. The clinical presentation was disconcerting for
MF, but assorted biopsies showed only a polyclonal ex-
pansion of CD8+ lymphocytes infiltrating the dermis,
epidermis and lymph nodes and no clonal gene rear-
rangements. The specter of DILS was heightened when
flow cytometry of peripheral blood lymphocytes revealed
a profound reversal of the CD4+:CD8+ cell ratio with a
marked expansion of CD8+ cells. Despite receiving
HAART, the patient succumbed to complications of me-
thicillin-resistant Staphylococcus aureus (MRSA) septi-
cemia. Herein, we alert readers to the hallmarks of this
unusual condition and review mimics that can be con-
fused with ACLD.
2. Case Report
In 1989, a 43-year-old Caucasian man who had sex with
other men tested HIV seropositive and subsequently re-
ceived zidovudine monotherapy. When HAART became
readily available in 1996, he was switched to a regimen
consisting of stavudine, lamivudine and nevirapine. Over
the ensuing years, he had a consistently non-detectable
HIV viral load, and he continued to work full time as a
registered nurse. His CD4+ count remained low, typi-
cally hovering between 60 - 110 cells/uL.
The patient sought medical attention for a nonspecific
lower extremity skin rash which was treated with topical
triamcinolone with benefit. Six months later, he was
again seen by a dermatologist after he noted progressive
facial erythroderma. When the rash failed to improve
despite the implementation of various topical agents and
the cessation of prophylactic trimethoprim-sulfameth-
oxazole, a series of skin biopsies were obtained. These
showed features of epidermal hyperplasia with elongated
and thickened rete pegs, confluent parakeratosis and
small collections of neutrophils within the stratum
corneum and moderately dense, superficial perivascular
lymphocytic inflammatory infiltrates (Figure 1). Im-
munofluorescence studies did not reveal a clonal disorder.
Subsequent computerized tomograms of the neck, chest,
abdomen and pelvis showed modest adenopathy involv-
ing the left axilla and right groin. There were no pulmo-
nary abnormalities.
Over the next several months, the patient received
topical and oral corticosteroids, oral retinoic acid, oral
methotrexate, as well as intravenous infliximab. How-
ever, none of these interventions led to significant or
consistent benefit. The patient temporarily stopped
HAART for three weeks to see if this strategy would
curtail the erythroderma which had now progressed to
involve his trunk and extremities. There was no signifi-
cant improvement in the degree of pruritus or in the
thickness or erythema of his skin, and thus, he restarted
HAART with efavire nz su bstituted for nevi r a pine.
He was referred to medical oncology and hematology
for additional evaluation after losing seven kilograms
over the ensuing three months. He described severe and
unrelenting pruritus which prevented him from sleeping
despite multiple trials with sleep medications, anxiolytics,
antihistamines and an anti-psychotic agent. He did not
experience night sweats or fevers except when he con-
tracted MRSA cellulitis of the hand. With oral antib iotics,
the infection and fevers resolved. His physical exam was
notable for proximal muscle atrophy and diffuse
erythroderma most prominent on the nape of neck, trunk
and feet and without preference for light-exposed areas
(Figures 2(a)-(c)). Multiple excoriations and scabbed
lesions involved all four extremities, but he was without
overt cellulitis or skin desquamation. There was no vis-
ceromegaly and only modest axillary and groin lympha-
denopathy. Laboratory studies included a white blood
count (WBC) of 23,000 with hematocrit of 42% and
platelet count of 326,000. Despite the use of steroids (50
mg daily), the WBC was comprised principally of lym-
phocytes. His chemistry and liver function tests were
Figure 1. Histological sections of epidermal biopsy show
features of hyperplasia with elongated and thickened rete
pegs, confluent parakeratosis and small collections of neu-
trophils within the stratum corneum and moderately dense,
superficial perivascular lymphocytic inflammatory infil-
trate. Figure 1 shows CD8+ lymphocytic infiltrates with
Hemotoxylin and Eosin stain.

Atypical Cutaneous Ly mphoproliferative Disorder: A Fatal Mimic of Cutaneous
T-Cell Lymphoma in a Patient with HIV Infec tion
12
Figure 2. (a)-(c) Clinical features in patient presented with dry and thickened skin with diffuse, pigmented, pruriginous
erythroder ma and desquamation most prominent on the nape of neck, feet and back.
to his regimen of hydroxyurea. Over the next several
weeks, his skin began to improve markedly with less
erythroderma and less keratosis and ulceration. Two
months later, his CD4+ count had dropped from a zenith
of 1035 to 295 cells/uL and his CD8+ count decr eased to
1601 cells/uL. While recuperating in a skilled nursing
facility, he became acutely hypotensive and febrile.
Blood cultures grew out MRSA. His condition rapidly
deteriorated, and his request to be transitioned to strict
comfort care was honored. He died shortly thereafter and
an autopsy was not performed.
within normal limits, but a serum lactate dehydrogenase
was 347 IU/L (normal < 252). A serum protein electro-
phoresis did not reveal a monoclonal band. When che-
cked for the first time in six months, his CD4+ count had
increased dramatically to 598 cells/uL and his CD8+
count was profoundly elevated to 13,333 cells/uL with a
CD4:CD8 ratio that was markedly inverted at .045 (nor-
mal, 1.7). His HIV-1 RNA viral load remained non-de-
tectable at less than 75 copies/mL. He was advised to
taper his corticosteroids and begin hydroxyurea at a dose
of 1000 mg daily.
One month later, the patient was hospitalized with
MRSA pneumonia. Shortly after his infection resolved,
mycophenolate mofetil, 1000 mg twice daily, was added
3. Discussion
Defining characteristics of ACLD in patients with im-

Atypical Cutaneous Ly mphoproliferative Disorder: A Fatal Mimic of Cutaneous
T-Cell Lymphoma in a Patient with HIV Infec tion 13
munosuppression are diffuse erythrodermatous plaques
comprised of polyclonal CD8+ predominant lymphocytes
which most often involve skin, accompanied by general-
ized lymphadenopathy, severe pruritus and depletion of
peripheral blood CD4+ lymphocytes. These findings are
in contrast to DILS where cutaneous disease is not com-
mon but a proclivity to involve th e parotid glands is to be
expected. The incidence of HIV-associated DILS is low,
3% in the United States [8]. The incidence of ACLD is
even rarer, with only 39 reported cases of individuals
with HIV described in the medical literature since 1992
[5].
The differential diagnosis of pruritus and diffuse ery-
throderma in a patient with HIV infection is broad and
may include scabies, papular pruritic eruption of HIV,
eosinophilic pustular folliculitis and drug reactions
[9-13]. In the context of weight loss, mild adenopathy,
and absence of a drug reaction or an infection, the patient
was referred to medical hematology and oncology to rule
out a paraneoplastic skin condition, MF or an alternative
cutaneous T-cell lymphoma (CTCL), including Sézary’s
syndrome and adult T-cell leukemia/lymphoma (ATLL).
With each of these conditions, symptoms of fever, night
sweats and weight loss may be prominent [14-18]. In
addition, generalized erythroderma, lymphadenopathy,
atypical T-cells in peripheral blood and hepatosple-
nomegaly may dominate the clinical presentation with
each of these conditions. However, upon further inspec-
tion of the clonal origins of the T-cells in MF showcases
resident effector memory T-cells. Sézary syndrome is
associated with central memory T-cells and ATLL is
associated with mature helper T-cells. All of these cells
are CD4+ lymphocytes [19-21]. In contrast, with ACLD,
representative biopsies of involved skin and lymph nod es
show that the infiltrates are comprised of mostly cyto-
toxic CD8+ T-cells [22-24] (Table 1).
The pathogenesis of ACLD has not been fully charac-
terized. However, a possible explanation of this condition
isthe expansion of cytotoxic CD8+ T-cells may be re-
lated to the diminished numbers of circulating CD4+ T-
cells and the reciprocal regulatory processes between the
two different cell types [2]. When there is marked deple-
tion of CD4+ T-cells and a large increase in CD8+ T-
cells, the regulatory balance is no longer intact and un-
controlled cytotoxic CD8+ cell expansion may occur
[2,25]. Remission of skin symptoms after HAART initia-
tion suggests the reduction of HIV viral load and the re-
constitution of CD4+ T-lymphocytes can exert regulatory
effects on the expansion of CD8+ cells [2]. Thus, ACLD
is not driven by a malignant condition, but rather, it is a
disease that is reactive in nature and can improve secon-
dary to HAART effects on HIV viral load [2]. The fac-
tors that further lead to the migration of CD8+ cells to
involve the dermis, however, remain unexplained.
There is no clear treatment for ACLD save HAART.
In the eight cases reported by Sbidian and colleagues and
the one case described by Egbers and colleagues, the
earliest response occurred within two weeks of initiation
of HAART, and the median time to maximal response
was five months after exposure to HAART [2,5]. It is
important that the hallmarks of ACLD are recognized
and the diagnosis is made early in the course of the dis-
ease to minimize suffering and poten tially fatal infections
[9]. Of the reported cases, more than half of the patients
died within one year of initial presentation of ACLD, but
the causes of death were secondary to other complica-
tions of AIDS; none died directly from this condition or
from malignancy [5]. Our patient was unique. He had
long been on effective HAART as evidenced by a con-
sistently non-detectable HIV viral load when he was di-
agnosed with ACLD with an elevated CD4+ count which
may be due to an aberrant immune reconstitution. He
showed signs of improvement only after he received cy-
toreductive (hydroxyurea) and immunosuppressive (my-
cophenolate mofetil) treatment and while corticosteroids
were in the process of being weaned.
Table 1. Comparison between ACLD and other malignant diseases that are associated with infiltrating lymphocytes, lym-
phadenopathy and erythroderma and treatment.
Variables ACLD DILS CTCL: MF CTCL: SS ATLL
Enlargement of
glands or organs General lymphadenopathy
Bilateral parotid
enlargements,
generalized
lymphadenopathy
Hepatosplenomegaly,
generalized
lymphadenopathy
Generalized
lymphadenopathy Generalized lymphadenopathy
Erythroderma Scabbed keratosis and diffuse pigmented
pruriginous lesio ns Not reported Fixed patches and
lesions mainly
photodistributed
Fixed patches and
lesions mainly
photodistributed Fixed patches and lesions
Infiltrating lymphocytic
phenotype CD8+ T-lymphocytes CD8+ T-lymphocytes CD4+ T-lymphocytesCD4+ T-lymphocytes CD4+ T-lymphocytes
Treatment HAART HAART Radiation therapy,
topical corticosteroids
Photochemotherapy,
topical
chemotherapy
Multiagentchemotherapy
often married to
interferons
ACLD = atypical cutaneous lymphoproliferative disorder; DILS = diffuse infiltrative lymphocytosis syndrome; CTCL: MF = cutaneous T-cell lymphoma:
Mycosis Fungoides. SS = Sézary’s Syndrome; ATLL = adult T-cell lymphoma/leukemia, and HAART = highly active antiretroviral therapy.

Atypical Cutaneous Ly mphoproliferative Disorder: A Fatal Mimic of Cutaneous
T-Cell Lymphoma in a Patient with HIV Infec tion
14
4. Conclusion
We alert healthcare providers to this rare HIV-associated
condition. The broad differential of severe and diffuse
erythroderma in the backdrop of HIV infection, the
problematic and potentially life-threatening nature of
severe and diffuse ACLD, the stereotypical changes in
peripheral blood T-lymphocyte subsets in absence of an
obvious clonal disorder of lymphocytes, the potential
beneficial effect of HAART and alternative options to
treat ACLD are central points to note.
REFERENCES
[1] H. Bachelez, F. Hadida, C. Parizot, et al., “Oligoclonal
Expansion of HIV-Specific Cytotoxic CD8 T Lympho-
cytes in the Skin of HIV-1-Infected Patients with Cuta-
neous Pseudolymphoma,” The Journal of Clinical Inves-
tigation, Vol. 101, No. 11, 1998, pp. 2506-2516.
doi:10.1172/JCI1450
[2] E. Sbidian, M. Battistella, J. Rivet, H. Bachelez, et al.,
“Remission of Severe CD8+ Cytotoxic T Cell Skin Infil-
trative Disease in Human Immunodeficiency Virus-Infe-
cted Patients Receiving Highly Active Antiretroviral
Therapy,” Clinical Infectious Diseases, Vol. 51, No. 6,
2010, pp. 741-748. doi:10.1086/655895
[3] T. A. Longacre, K. Foucar, F. Koster and W. Burgdorf,
“Atypical Cutaneous Lymphoproliferative Disorder Re-
sembling Mycosis Fungoides in AIDS,” The American
Journal of Dermatopathology, Vol 11, No. 5, 1989, pp.
451-456. doi:10.1097/00000372-198910000-00007
[4] S. Itescu, J. Dalton, H. Z. Zhang and R. Winchester,
“Tissue Infiltration in a CD8 Lymphocytosis Syndrome
Associated with Human Immunodeficiency Virus-1 In-
fection Has the Phenotypic Appearance of an Antigeni-
cally Driven Response,” Journal of Clinical Investigation,
Vol. 91, No. 5, 1993, pp. 2216-2225.
doi:10.1172/JCI116448
[5] R. G. Egbers, T. T. Do, L. Su, Y. R. Helfrich, J. E. Gud-
jonsson, “Rapid Clinical Change in Lesions of Atypical
Cutaneous Lymphoproliferative Disorder in an HIV Pa-
tient: A Case Report and Review of the Literature,” Der-
matology Online Journal, Vol. 17, No. 9, 2011, p. 4.
[6] J. R. Golbus, G. Gallagher, G. Blackburn and S. Cinti,
“Polyneuropathy Associated with the Diffuse Infiltrative
Lymphocytosis Syndrome,” Journal of the International
Association of Providers of AIDS Care, Vol. 11, No. 4,
2012, pp. 223-226. doi:10.1177/1545109712442798
[7] D. Basu, F. M. Williams, C. W. Ahn and J. D. Reveille,
“Changing Spectrum of the Diffuse Lymphocytosis Syn-
drome,” Arthritis Care and Research, Vol. 55, No. 3,
2006, pp. 466-472. doi:10.1002/art.21980
[8] P. F. Levay and M. E. Motes, “Diffuse Infiltrative Lym-
phocytosis Syndrome (DILS),” South African Family
Practice, Vol. 50, No. 2, 2008, pp. 42-44.
[9] S. Friedler, M. T. Parisi, E. Waldo, R. Wieczorek, G.
Sidhu and M. J. Rico, “Atypical Cutaneous Lymphopro-
liferative Disorder in Patients with HIV Infection,” In-
ternational Journal of Dermatology, Vol. 38, No. 2, 1999,
pp. 111-118. doi:10.1046/j.1365-4362.1999.00417.x
[10] W. D. James, R. R. Redfield, G. P. Lupton, et al., “A
Papular Eruption Associated with Human T Cell Lym-
photropic Virus Type III Disease,” Journal of the Ameri-
can Academy of Dermatology, Vol. 13, No. 4, 1985, pp.
563-566. doi:10.1016/S0190-9622(85)70197-1
[11] N. S. Sadick and N. S. McNutt, “Cutaneous Hypersensi-
tivity Reactions in Patients with AIDS,” International
Journal of Dermatology, Vol. 32, No. 9, 1993, pp. 621-627.
doi:10.1111/j.1365-4362.1993.tb04014.x
[12] M. R. Buchness, H. W. Lim, V. A. Hatcher, et al., “Eosi-
nophilic Pustular Folliculitis in the Acquired Immunode-
ficiency Syndrome,” The New England Journal of Medi-
cine, Vol. 318, No. 18, 1988, pp. 1183-1186.
doi:10.1056/NEJM198805053181807
[13] S. A. Coopman, R. A. Johnson, R. Platt and R. S. Stern,
“Cutaneous Disease and Drug Reactions in HIV Infec-
tion,” The New England Journal of Medicine, Vol. 328,
No. 23, 1993, pp. 1670-1674.
doi:10.1056/NEJM199306103282304
[14] T. Nagatani, “Adult T-Cell Leukemia/Lymphoma Cuta-
neous Type,” International Journal of Dermatology, Vol.
35, No. 6, 1996, pp. 400-401.
doi:10.1111/j.1365-4362.1996.tb03018.x
[15] F. Gahongayire, “Mycosis Fungoides and Sézary Syn-
drome against a Human Immunodeficiency Virus-Posi-
tive Background: Case Report,” International Journal of
Dermatology, Vol. 46, No. 1, 2007, pp. 32-35.
[16] R. Willemze, “Primary Cutaneous Lymphomas,” Annals
of Oncology, Vol. 22, No. 4, 2011, pp. iv72-iv75.
doi:10.1093/annonc/mdr181
[17] E. A. Kotz, D. Anderson and B. H. Thiers, “Cutaneous
T-Cell Lymphoma,” Journal of the European Academy of
Dermatology and Venereology, Vol. 17, No. 2, 2003, pp.
131-137. doi:10.1046/j.1468-3083.2003.00635.x
[18] T. Takahashi, H. Tsukuda, H. Itoh, M. Tsujisaki, et al.,
“Primary and Isolated Adult T-Cell Leukemia/Lymphoma
of the Bone Marrow,” The Japanese Society of Internal
Medicine, Vol. 50, No. 20, 2011, pp. 2393-2396.
doi:10.2169/internalmedicine.50.5857
[19] J. J. Campbell, R. A. Clark, R. Watanabe and T. S. Kup-
per, “Sézary Syndrome and Mycosis Fungoides Arise
from Distinct T-Cell Subsets: A Biologic Rationale for
Their Distinct Clinical Behaviors,” Blood, Vol. 116, No.
5, 2010, pp. 767-771. doi:10.1182/blood-2009-11-251926
[20] K. Takatsuki, “Discovery of Adult T-Cell Leukemia,”
Retrovirology, Vol. 2, No. 16, 2005, pp. 16-18.
[21] M. Duvic, M. Donato, B. Dabaja, C. Hosing, et al., “Total
Skin Electron Beam and Non-Myeloablative Allogeneic
Hematopoietic Stem-Cell Transplantation in Advanced
Mycosis Fungoides and Sézary Syndrome,” Journal of
Clinical Oncology, Vol. 28, No. 14, 2010, pp. 2365-2372.
doi:10.1200/JCO.2009.25.8301
[22] M. Janier, C. Katlama, B. Flageul, et al., “The Pseu-
do-Sézary-Syndrome with CD8 Phenotype in a Patient

Atypical Cutaneous Ly mphoproliferative Disorder: A Fatal Mimic of Cutaneous
T-Cell Lymphoma in a Patient with HIV Infec tion
15
with the Acquired Immunodeficiency Syndrome (AIDS),”
Annals of Internal Medicine, Vol. 110, No. 9, 1989, pp.
738-740.
[23] P. Zhang, L. Chiribogy, M. Jacobsen, et al., “Mycosis
Fungoides-Like T-Cell Cutaneous Lymphoid Infiltrates in
Patients with HIV Infection,” American Journal of Der-
matopathology, Vol. 17, No. 1, 1995, pp. 29-35.
[24] H. Bachelez, F. Hadida and G. Gorochov, “Massive Infil-
tration of the Skin by HIV-Specific Cytotoxic CD8+
Cells,” The New England Journal of Medicine, Vol. 335,
No. 1, 1996, pp. 61-62.
doi:10.1056/NEJM199607043350118
[25] M. E. Moreno-Fernandez, W. Zapata, J. T. Blackard, G.
Franchini and C. A. Chougnet, “Human Regulatory T
Cells Are Targets for Human Immunodeficiency Virus
Infection, and Their Susceptibility Differs Depending on
the HIV Type 1 Strain,” Journal of Virology, Vol. 83, No.
24, 2009, pp. 12925-12933. doi:10.1128/JVI.01352-09