BRIEF REPORTS

Protease inhibitor-associated angiolipomatosis

Jan I? Dank, MD, and Roy Colven, MD Seattle, Washington

Treatment with protease inhibitors in some persons infected with HIV-l is associated with a syndrome of
lipodystrophy manifesting as peripheral lipoatrophy, relative central adiposity, insulin resistance, and serum
lipid abnormalities. We report 3 cases of HIV-l infected patients who experienced symptomatic
angiolipomas shortly after starting antiretroviral therapy including the protease inhibitor indinavir. The
mechanism behind this observation may be similar to that of previously reported protease
inhibitor-associated fat redistribution, but instead involving the adipose tissue of discrete uncommon
benign tumors. (J Am Acad Dermatol2000;42:129-31.)

T reatment of persons infected with HIV-1 with

protease inhibitors has been associated with a
syndrome of peripheral lipodystrophy, cen-
tral adiposity, breast hypertrophy, hyperlipidemia,
sue consistent with an angiolipoma. He subsequent-
ly had 2 more nodules removed that showed similar
histology.

and insulin resistance.1.5 We report 3 cases of HIV-l- Case 2

infected patients who experienced symptomatic A 34-year-old Hispanic homosexual man with
angiolipomas, benign tumors of adipose tissue, stage A2 HIV infection had a medical history signifi-
shortly after beginning antiretroviral therapy includ- cant for hepatitis B and idiopathic thrombocytopenic
ing the protease inhibitor indinavir. All previous purpura. One year before presentation he had begun
reports of fat redistribution associated with protease antiretroviral therapy including zidovudine, lamivu-
inhibitors involve symptomatic and asymptomatic dine, and indinavir. Four to six weeks before presen-
accumulations of fat in normal adipose tissues. This tation he had noticed 3 tender upper extremity
observation may involve a similar mechanism, but masses. Examination revealed firm, subcutaneous
involving the adipose tissue of discrete uncommon masses slightly tender to palpation, 2 on the left arm
benign tumors. and 1 on the left forearm. Neither he nor his physi-
cians noted any redistribution of weight or fat. All 3
CASE REPORTS masses were excised. Histologic examination of all 3
Case 1 showed reactive adipose tissue with foci of increased
A 49-year-old white bisexual man with stage A, vascular tissue consistent with angiolipomas.
HIV infection and history of ethanol abuse had at
least 1 pre-existing asymptomatic subcutaneous nod- Case 3
ule on an extremity present for at least several years. A 34-year-old white homosexual man with stage
Five to six months after adding indinavir to an exist- B, HIV infection noticed the appearance of multiple
ing regimen of zidovudine and lamivudine, he tender subcutaneous nodules, primarily on the
noticed the appearance of multiple, often tender, extremities, but also on the trunk about 6 to 7
subcutaneous nodules, primarily on the upper months after starting protease inhibitors (Fig 1).
extremities, but also on the abdomen and thighs. Neither he nor his physicians observed any redistrib-
Coincident with this was growth of fat in the abdom- ution in fat or weight over the same period. His anti-
inal area. Excision of the most symptomatic mass on retroviral regimen has included, sequentially,
the right arm showed on histologic examination a saquinavir, indinavir, and nelfinavir. At the time of
proliferation of small blood vessels and adipose tis- referral for the soft tissue masses he was taking indi-
navir. He has had excisions of 4 subcutaneous mass-
From the Department of Medicine, Division of Dermatology, es with histopathology consistent with angiolipoma
University of Washington-Harborview Medical Center.
(Fig 2).
Reprint requests: Roy Colven, MD, 325 9th Ave, University of
Washington-Harborview Medical Center, Department of
Medicine-Division of Dermatology, Seattle,WA 98104. DISCUSSION
Copyright 0 2000 by the American Academy of Dermatology, Inc. A temporal association between the starting of
0190-9622/2000/$12.00 + 0 16/54/l 01896 protease inhibitors and indinavir in particular has

129
130 Brief reports J AM ACADDERMATOL
JANUARY
2000

Fig 1. Patient 3. A, Forearm shows at least 3 tender, firm subcutaneous masses.B, Excision of
mass.

Fig 2. Patient 3. Photomicrograph of biopsy specimen of mass shows proliferation of both

adipocytes and small blood vessels.

been associated with a “buffalo hump” pattern of fat and increased triglyceride levels in patients receiving
accumulation in the cervical fat pad area and across indinavir has been correlated to increases in visceral
the shoulders and back in patients without adipose tissue as measured by computed tomo-
Cushing’s syndrome. l Increased abdominal girth graphic scans comparing ratios of total adipose tis-
J AM ACAD DERMATOL Brief reports 13 1
VOLUME 42, NUMBER 1. PART 1

sue to visceral adipose tissue. The syndrome appears lar to that reported for the appearance of central fat
to be a redistribution of body fat because the redistribution after beginning protease inhibitors. In
patients affected did not gain a significant amount of one patient the presence of at least one of the sub-
weight after starting indinavir.2 One study of 116 cutaneous lesions was known to predate the initia-
patients receiving protease inhibitors found a syn- tion of indinavir, but that lesion, as well as others not
drome of lipodystrophy, hyperlipidemia, and insulin previously noted, grew in size and became painful
resistance in 64% of patients taking protease only after the onset of therapy. Like visceral fat,
inhibitors.3 The syndrome develops more rapidly breast adipose tissue, and the fat pad of the upper
and profoundly in patients taking a combination of back and shoulders, the adipose tissue found in
both ritonavir and saquinavir than in those receiving angiolipomas may be a preferential site for fat redis-
indinavir.3 Hypertrophy of breast tissue has also tribution in the presence of protease inhibitors.
been reported in female and male patients. Painful Although an association based on a limited number
breast hypertrophy is apparently reversible with dis- of case reports must be treated with caution, the
continuation of the drug.4 The mechanism by which temporal association in the cases reported makes
protease inhibitors might cause the lipodystrophy the association plausible. If this association between
syndrome is not clear. Protease inhibitors are known angiolipomas and protease inhibitors is confirmed
inhibitors of cytochrome P-450 3A. According to one by the observations of others, it represents not only
hypothesis, the protease inhibitors may impair the a newly reported minor complication of drug thera-
generation of cis-9-retinoic acid by cytochrome P-450 py, but also a potential model for studying the mech-
3A in peripheral adipocytes, resulting in impaired fat anism of the lipodystrophy syndrome itself.
storage and lipid release in the peripheral
adipocytes, the more metabolically active central REFERENCES
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firmer and often painful or tender. Histologically indinavirlancet 1998;351:871-5.
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angiolipomas consist of a mixture of two mesenchy-
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mas, spindle cell lipoma, Kaposi’s sarcoma, and spin- breasts in a patient treated with indinavir. Clin Infect Dis
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lipomas usually have karyotypic abnormalities HIV-l protease inhibitor-associated peripheral lipodystrophy,
involving 2q, Gp, and 13q, angiolipomas normally hyperlipidaemia, and insulin resistance. Lancet 1998;352:1881-
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In our patients the symptomatic appearance of N,et al.Cytogenetic analysis of subcutaneous angiolipoma:fur-
the lesions followed the initiation of protease ther evidence supporting its difference from ordinary pure
inhibitors by many months. This time course is simi- lipomas. Am J Surg Pathol 1997;21:441-4.