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BRIEF REPORTS

Protease inhibitor-associated angiolipomatosisJan 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 oflipodystrophy manifesting as peripheral lipoatrophy, relative central adiposity, insulin resistance, and serumlipid abnormalities. We report 3 cases of HIV-l infected patients who experienced symptomaticangiolipomas shortly after starting antiretroviral therapy including the protease inhibitor indinavir. Themechanism behind this observation may be sim ilar to that of prev iously reported proteaseinhibitor-associated fat redistribution, but instead involving the adipose tissue of discrete uncommonbenign tumors. (J Am Acad Dermatol2000;42:129-31.)

T eatment of persons infected with HIV-1 withprotease inhibito rs has been associa ted with asyndrome of peripheral lipodystrophy, cen-tral adiposity, breast hypertrophy, hyperlipidemia,and insulin resistance.1.5 We report 3 cases of HIV-l-infected patients who experienced symptomaticangiolipomas, benign tumors of adipose tissue,shortly after beginning antiretroviral therapy includ-ing the protease inhibitor indinavir. All previousreports of fat redistribution associa ted with proteaseinhibitors involve symptomatic and asymptomaticaccumulations of fat in normal adipose tissues. Thisobservation may involve a similar mechanism, butinvolving the adipose tissue of discrete uncommonbenign tumors.CASE REPORTSCase 1

A 49-year-old white bisexual man with stage A,HIV infection and history of ethanol abuse had atleast 1 pre-existing asymptomatic subcutaneous nod-ule on an extremity present for at least several years.Five to six months after adding indinavir to an exist-ing regimen of zidovudine and lamivudine, henoticed the appearance of multiple, often tender,subcutaneous nodules, primarily on the upperextremities, but also on the abdomen and thighs.Coincident with this was growth of fat in the abdom-inal area. Excis ion of the most symptomatic mass onthe right arm showed on histologic examination aproliferation of small blood vesse ls and adipose tis -From the Departme nt of Med icine, Division of Dermatology,

Universi ty of Washington-Harborview Med ical Center.Reprint requests: Roy Colven, MD, 325 9th Ave, Universi ty of

Washington-Harborview Med ical Center, Departme nt ofMedic ine-Div is ion of Dermatology, Seat t le,WA 98104.

Copyr ight 0 2000 by the Amer ican Academy of Dermatology, Inc.0190-9622/2000/$12.00 + 0 16/54/ l 01896

sue consistent with an angiolipoma. He subsequent-ly had 2 more nodules removed that showed sim ilarhistology.Case 2

A 34-year-old Hispanic homosexual man withstage A2 HIV infection had a medical history signifi-cant for hepatitis B and idiopathic thrombocytopenicpurpura. One year before presentation he had begunantiretroviral therapy including zidovudine, lamivu-dine, and indinavir. Four to six weeks before presen-tation he had noticed 3 tender upper extremitymasses. Examination revealed firm, subcutaneousmasses slightly tender to palpation, 2 on the left armand 1 on the left forearm. Neither he nor his physi-cians noted any redistribution of weight or fat. All 3masses were excised. Histologic examination of all 3showed reactive adipose tissue with foci of increasedvascular tissue consistent with angiolipomas.Case 3

A 34-year-old white homosexual man with stageB, HIV infection noticed the appearance of multipletender subcutaneous nodules, primarily on theextremities, but also on the trunk about 6 to 7months after starting protease inhibitors (Fig 1).Neither he nor his physicians observed any redistrib-ution in fat or weight over the same period. His anti-retroviral regimen has included, sequentially,saquinavir, indinavir, and nelfinavir. At the time ofreferral for the soft tissue masses he was taking indi-navir. He has had excisions of 4 subcutaneous mass-es with histopathology consistent with angiolipoma(Fig 2).DISCUSSIONA temporal assoc iation between the starting ofprotease inhibitors and indinavir in particular has

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

Fig 2. Patient 3. Photomicrograph of biopsy specimen of mass shows proliferation of bothadipocytes and small blood vessels.

been associated with a buffalo hump pattern of fat and increased triglyceride levels in patients receivingaccumulation in the cervical fat pad area and across indinavir has been correlated to increases in visce ralthe shoulders and back in patients without adipose tissue as measured by computed tomo-Cushings syndrome. l Increased abdominal girth graphic scans comparing ratios of total adipose tis-

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sue to viscera l adipose tissue. The syndrome appearsto be a redistribution of body fat because thepatients affected d id not gain a significant amount ofweight after starting indinavir.2 One study of 116patients receiving protease inhibitors found a syn-drome of lipodystrophy, hyperlipidemia, and insulinresistance in 64% of patients taking proteaseinhibitors.3 The syndrome develops more rapidlyand profoundly in patients taking a combination ofboth ritonavir and saquinavir than in those receivingindinavir.3 Hypertrophy of breast tissue has alsobeen reported in female and male patients. Painfu lbreast hypertrophy is apparently reversible with dis-continuation of the drug.4 The mechanism by whichprotease inhibitors might cause the lipodystrophysyndrome is not clear. Protease inhibitors are knowninhibitors of cytochrome P-450 3A. According to onehypothesis, the protease inhibitors may impair thegeneration of cis-9-retinoic acid by cytochrome P-4503A in peripheral adipocytes, resulting in impaired fatstorage and lipid release in the peripheraladipocytes, the more metabolically active centraladipocytes accumulating fat by default.5

Angiolipomas are uncommon, though not rare,soft tissue tumors. They can be multiple and familial.Clinically they are similar to lipomas, but tend to befirmer and often painful or tender. Histo logicallyangiolipomas consist of a mixture of two mesenchy-ma1 elements, adipose cells and small blood vessels,with the ratio of vesse l to fat highly variable.Histologically, they can be distinguished from lipo-mas, spindle cell lipoma, Kaposis sarcoma, and spin-dle cel l hemangioendothelioma.6 Whereas ordinarylipomas usually have karyotypic abnormalitiesinvo lving 2q, Gp, and 13q, angiolipomas normallyshow normal karyotypes. This has suggested tosome that they may be considered to be hamar-tomatous lesions rather than true neoplasms.7

In our patients the symptomatic appearance ofthe lesions followed the initiation of proteaseinhibitors by many months. This time course is simi-

Brief reports 13 1

lar to that reported for the appearance of central fatredistribution after beginning protease inhibitors. Inone patient the presence of at least one of the sub-cutaneous lesions was known to predate the initia -tion of indinavir, but that lesion, as well as others notpreviously noted, grew in size and became painfulonly after the onset of therapy. Like visce ral fat,breast adipose tissue, and the fat pad of the upperback and shoulders, the adipose tissue found inangiolipomas may be a preferential site for fat redis-tribution in the presence of protease inhibitors.Although an assoc iation based on a limited numberof case reports must be treated with caution, thetemporal association in the cases reported makesthe association plausible. If this association betweenangiolipomas and protease inhibitors is confirmedby the observations of others, i t represents not onlya newly reported minor complication of drug thera-py, but also a potential model for studying the mech-anism of the lipodystrophy syndrome itself.REFERENCES

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Hengel RL, Watts NB, Lennox JL. Benign symmetric lipomatosisassociated with protease inhibitors [letter]. Lancet 1997;350:1596.Miller KD,Jones E,Yandovski JA,Shankar R,Feuerstein I, FalloonJ. Visceral abdominal-f at accumulation associated with use ofindinavirlancet 1998;351:871-5.Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al.A syndrome of peripheral lipodystrophy, hyperlipidaem ia andinsulin resistance in patients receiving HIV protease inhibitors.AIDS 1998;12:F5-F58.Herry I, Bernard L, de Truchis P, Perrone C. Hypertrophy of thebreasts in a patient treated with indinavir. Clin Infect Dis1997;25:937-8.Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis ofHIV-l protease inhibitor-associated peripheral lipodystrophy,hyperlipidaem ia, and insulin resistance. Lancet 1998;352:1881-3.Allen PW.Recent advances in tumors of adipose tissue.CurrTopPathol 1995;89:215-39.Sciot R,Akerman M, Dal Cin P,Wever ID, Fletcher CDM, MandahlN,et al.Cytogenetic analysis of subcutaneous angiolipoma:fu r-ther evidence supporting its difference from ordinary purelipomas. Am J Surg Pathol 1997;21:441-4.