J Oral Maxillofac Surg65:2095-2099, 2007

Oral Lipomatosis in AntiretroviralTherapy–Associated Lipodystrophy

SyndromeKishore Shetty, DDS*

Human immunodeficiency virus (HIV) has indirectlyclaimed the lives of over 3 million people to date, andmore than 40 million people worldwide are currentlyinfected with HIV.1 HIV preferentially infects CD4�Tlymphocytes, resulting in a progressive depletion ofthese cells. This leads to immunodeficiency and sub-sequent opportunistic infections, including oral infec-tions. Half of all people infected with HIV experiencean oral opportunistic infection within 5 years of HIVseroconversion.2 While opportunistic infections ofthe oral cavity are usually not life threatening, they dolead to significant morbidity and health care costs forindividuals infected with HIV.

The availability of potent antiretroviral therapieshas greatly improved treatment of HIV, reducing mor-tality and prolonging survival for people infected withHIV in industrialized countries. These medication reg-imens are referred to as highly active antiretroviraltherapies (HAART), and typically consist of 3 drugs (2of which are nucleoside analogue reverse transcrip-tase inhibitors, and 1 of which is either a non-nucle-oside reverse transcriptase inhibitor or a proteaseinhibitor [PI] or a cell fusion inhibitor) (Table 1).HAART has been responsible for decreasing HIVplasma viral loads, increasing CD4�T lymphocytecounts, prolonging the progression to acquired immu-nodeficiency syndrome (AIDS), and decreasing mor-tality from HIV.3

In the past several years since the introduction ofHAART and PIs, there have been reports of unusual orabnormal fat distribution, body habitus changes, andhyperlipidemia in patients infected with HIV.4 Recog-

nition of these unusual changes in body shape oftencomes about when patients express serious concernsabout such changes.4-6 The syndrome of unusual bodyshape changes is referred to by various terms, including“fat redistribution,” “lipodystrophy,” and “dysmorphia.”To date, no exact case definition of the syndrome hasbeen developed. In 1998, Carr et al7 described a newclinical phenomenon of lipodystrophy in patients in-fected with HIV. Their original description was of asyndrome characterized by peripheral lipoatrophy,hyperlipidemia, and insulin resistance in patients re-ceiving PIs for the treatment of HIV. Contemporane-ously, other body shape changes were described, in-cluding central adiposity and the presence of a buffalohump. We describe in detail 1 patient who presentedwith an unusual component of this syndrome: thedeposition of excess subcutaneous fat in the floor ofthe mouth. This variation in phenotype of the lipo-dystrophy syndrome may have treatment implicationsfor individual patients as well as considerations forpathogenesis.

Report of a Case

A 45-year-old HIV-positive Caucasian male presented tothe clinic for evaluation and treatment of a slowly growingmass in his mouth. The patient was diagnosed with HIV 8months earlier and started on a 4-drug regimen comprisedof stavudine, didanosine, indinavir, and ritonavir. His plasmaHIV RNA level prior to treatment was 120,000 copies/mL andhis nadir CD4� count was 25 cells/�L.

Although he tolerated his regimen relatively well, henoticed in increased swelling of his neck anteriorly andposteriorly after 6 months of treatment (Fig 1). The patientexperienced marked discomfort in relation to the anteriorswelling in his neck but no dysphagia, dyspnea, or symp-toms of obstructive sleep apnea. Over the last few weeks hestarted noticing a slowly growing mass on the floor of hismouth (Fig 2). The submucosal swelling measured 3.5 �2.5 cm in diameter, was soft to firm in consistency, non-tender, and became harder in consistency on protrusion ofthe tongue. There were no palpable lymph nodes in theneck.

His most recent CD4� count was 427 cells/�L, and hisplasma HIV RNA level �50 copies/mL. His liver function

*Director and Associate Professor, Medically Complex Patient

Clinic, The University of Texas, Health Science Center at Houston,

Houston, TX.

Address correspondence and reprint requests to Dr Shetty: Med-

ically Complex Patient Clinic, The University of Texas, Health

Science Center at Houston, 6516 M.D. Anderson Blvd, Suite 475,

Houston, TX 77030; e-mail: kishore.shetty@uth.tmc.edu

© 2007 American Association of Oral and Maxillofacial Surgeons

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doi:10.1016/j.joms.2006.05.046

KISHORE SHETTY 2095

test had shown an elevated alanine aminotransferase (ALT)of 3.5 times the upper limit of normal, and his low-densitylipoprotein (LDL) cholesterol level had increased to 170mg/dL (Table 2).

Cushing disease and thyroid disease were both excludedby formal testing, including thyroid function test and a24-hour urinary cortisol measurement. A dual energy X-rayabsorptiometry scan showed 28% abdominal fat, 36% armfat, and 11% leg fat. A computed tomography scan showedincreased subcutaneous fat in the anterior neck.

Fine needle aspiration cytology proved inconclusive andthe patient then decided to undergo an incisional biopsy

under local anesthesia. The histopathologic sectionsshowed sheets of mature fat cells infiltrating striated muscletissues (Figs 3, 4). The overlying squamous epithelium ap-peared intact and normal.

The case was diagnosed as intramuscular lipoma. Thepatient subsequently underwent a wide excisional biopsy ofthe lipomatous mass under general anesthesia with an un-eventful recovery. The patient did not have any recurrence

Table 1. ANTIRETROVIRAL DRUG LIST

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)Mechanism of action: Nucleoside analogues enter the cell and are phosphorylated by cellular kinases that convert themto their active triphosphate metabolite. Nucleotides differ from nucleosides because they possess a phosphate group.Once activated, they inhibit HIV-1 reverse transcriptase by competing with natural substrates and by incorporating intothe viral DNA. This process prevents chain elongation, which ultimately prevents HIV replication in infected cells.

Abacavir (ABC) Stavudine (d4T)Didanosine (ddl) Tenofovir (TDF)Emtricitabine (FTC) Zalitabine (ddC)Lamivudine (3TC) Zidovudine (ZDV or AZT)

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Mechanism of action: Similar to the nucleoside/nucleotide RTIs, these antiretroviral drugs also inhibit reversetranscriptase. They act, however, by noncompetitive inhibition, binding directly to reverse transcriptase, blockingRNA- and DNA-dependent polymerase activities.

Delavirdine (DLV) Nevirapine (NVP)Efavirenz (EFV)

Protease InhibitorsMechanism of action: These antiretroviral agents inhibit the enzyme protease. Protease is used to cleave viralpolyprotein precursors to generate functional proteins in HIV-infected cells. Protease inhibitors prevent HIV cellmaturation, infection of new cells, and viral replication.

Amprenavir (APV) Lopinavir (LPV)Atazanavir (ATV) Nelfinavir (NFV)Fosamprenavir (FPV) Ritonavir (RTV)Indinavir (IDV) Saquinavir (SQV)

Cell Fusion InhibitorsMechanism of action: Fusion inhibitors prevent the entry of HIV-1 into cells by inhibiting the fusion of viral and cellularmembranes.

Enfuvirtide (T-20)

Kishore Shetty. Oral Lipomatosis in Antiretroviral Therapy. J Oral Maxillofac Surg 2007.

FIGURE 1. Anterior and posterior views of patient showing lipodys-trophic changes including swelling in the anterior neck.

Kishore Shetty. Oral Lipomatosis in Antiretroviral Therapy. J OralMaxillofac Surg 2007.

FIGURE 2. Clinical photograph demonstrating a submucosal noduleon the floor of the mouth.

Kishore Shetty. Oral Lipomatosis in Antiretroviral Therapy. J OralMaxillofac Surg 2007.

2096 ORAL LIPOMATOSIS IN ANTIRETROVIRAL THERAPY

of the lipomatous mass on postoperative follow-up visits 6months postsurgery. The patient did not wish to undergoany surgical therapy for removal of the fat on the neck andthe back. The patient’s antiretroviral regimen was alteredwith the replacement of stavudine by abacavir. After 12weeks of switching from stavudine to tenofovir, triglycerideand cholesterol levels showed significant decreases, whichsuggests that such a switch may reverse, at least partly,stavudine-associated dyslipidemia. His plasma HIV RNAlevel at the 12-week follow-up was undetectable (�50 cop-ies/mL) with a CD4� count of 267 cells/�L.

Discussion

Lipodystrophy is defective metabolism or distribu-tion of fat. Most lipodystrophy syndromes are associ-ated with other metabolic disorders, particularly insu-lin resistance and hyperlipidemia. The characteristicsof this phenomenon in HIV-infected individuals arethe loss of subcutaneous fat and the abnormal accu-mulation of fat in unusual areas of the body, such asdeep inside the abdomen and on the back of theneck.8 Carr et al7 defined lipodystrophy by physicalexam and self-reports as loss of fat in the face, arms,and legs, with or without central adiposity. Donget al5 defined lipodystrophy as peripheral fat wasting;whereas Yanovski et al10 defined lipodystrophy by thepresence of an enlarged dorsocervical fat pad, in-

creased visceral abdominal fat, loss of facial fat, andbreast enlargement in women. It may be possible thatmore than 1 phenomenon is being observed. Theclinical manifestations of lipodystrophy syndrome inpatients infected with HIV include central or intra-abdominal adiposity,4 enlargement of the dorsocervi-cal fat pad (also known as a buffalo hump),10-12 breasthypertrophy in women and gynecomastia in men,13

bilateral symmetric lipomatosis,4 and loss of fat fromthe face, buttocks, and extremities.7,8 Shaw et al8

describe the effects of lipodystrophy syndrome asbenign changes in physical appearance rather thanserious health problems. However, other researcherssuggest that the syndrome may promote developmentof diabetes and cardiovascular disease.5,14

The severity of lipodystrophy can be graded on ascale developed as part of the HIV Outpatient Study(HOPS).15 The scale is as follows:

Grade 0: Absence of any lipodystrophy.Grade 1: Mild signs only noticeable on close inspection.Grade 2: Moderate lipodystrophy readily noticeable

by a patient or a health professional.Grade 3: Severe lipodystrophy readily noticeable by a

casual observer.

FIGURE 4. High power photomicrograph showing a benign prolif-eration of adipocytes and striated muscle tissue.

Kishore Shetty. Oral Lipomatosis in Antiretroviral Therapy. J OralMaxillofac Surg 2007.

Table 2. LIPID PROFILE DURING THE COURSE OF THE ANTIRETROVIRAL REGIMEN

CholesterolLow-DensityLipoprotein Triglycerides

High-Density

Lipoprotein

Prior regimen 186 mg/dL 128 mg/dL 202 mg/dL 45 mg/dLCurrent regimen 253 mg/dL 170 mg/dL 375 mg/dL 36 mg/dL

Kishore Shetty. Oral Lipomatosis in Antiretroviral Therapy. J Oral Maxillofac Surg 2007.

FIGURE 3. Medium power photomicrograph of an unencapsulatedbenign proliferation of adipose tissue.

Kishore Shetty. Oral Lipomatosis in Antiretroviral Therapy. J OralMaxillofac Surg 2007.

KISHORE SHETTY 2097

The HOPS scale is quite subjective and difficult tovalidate but is still useful to characterize lipodystrophy.

Hyperlipidemia

Several metabolic alterations, especially hypertri-glyceridemia, have been observed in patients withHIV-associated lipodystrophy.9 PI therapy is a riskfactor for developing hyperlipidemia.16 Carr et al17

reported hyperlipidemia in ranges associated withcardiovascular mortality in 74% of patients receivingPI therapy. Shaw et al8 reported elevated triglyceridelevels in a cohort of 12 patients with clinical manifes-tations of HIV-associated lipodystrophy, all of whomwere receiving PI therapy. Of the 12 patients, 5 hadelevated total cholesterol levels while 7 had totalcholesterol levels within the normal range. Silvaet al18 also reported significantly increased triglycer-ide levels after treatment with PIs (P � .0001). Donget al5 noted evaluated serum lipid levels in womenprior to HAART regimens and reported significantincreases in total cholesterol. These authors did notfind significant differences in serum lipid levels be-tween women who had complaints of body habituschanges and those who did not. These studies suggestthat the prevalence of hyperlipidemia is generallyhigh in patients receiving PI therapy regardless ofbody shape changes.

Body Weight and Body Composition

In many cases, the lipodystrophy syndrome producesweight loss. In an Australian study, Carr et al9 reportedweight loss of 0.5 kg per month in patients experiencinglipodystrophy syndrome. Yanovski et al10 found no gainin total body weight in patients with lipodystrophy syn-drome. Conversely, some cases of weight gain greaterthan 5 kg have been reported.5,11 Several investigatorshave conducted studies to evaluate fat redistributionresulting in body shape changes. Carr et al7 examinedtotal and subcutaneous fat distribution using dual en-ergy x-ray absorptometry (DEXA) in 3 groups: pa-tients on PIs, patients who had never had PIs, andhealthy controls. They reported that PI-naive patientshad body composition measurements similar to thoseof the controls. These researchers also found thatpatients experiencing lipodystrophy syndrome hadsignificantly lower body fat in all regions except theabdomen than those without the syndrome andhealthy controls. Hadigan et al19 assessed regionalbody composition using DEXA and reported in-creased truncal fat to extremity fat ratio and de-creased extremity fat in patients with HIV, comparedwith healthy controls. Silva et al18 evaluated the effectof PIs on weight and body composition in a group of27 patients, 90% of whom were men. They reported

a significant increase in weight (P � .0001) and bodymass index (P � .0001).

Lipodystrophy and Protease Inhibitors

Carr et al7 reported a syndrome of lipodystrophyand other metabolic changes in 74 (64%) of 116patients (98% of whom were men) receiving at least 1PI compared with only 1 (3%) of 32 patients who hadnever received PIs. These authors also found that withthe PI combination of saquinavir and ritonavir, thelipodystrophy syndrome was more severe and devel-oped earlier (8 months compared with 12 months)than with the PI indinavir alone. Shaw et al8 reportedthat patients on PI therapy who developed lipodys-trophy syndrome were significantly older than thoseon PI therapy who did not develop the syndrome(P � .016). Lipodystrophy syndrome has been ob-served in patients who were not receiving PIs. In astudy involving women infected with HIV, Hadiganet al19 found no significant differences in truncal ad-iposity or extremity fat in PI-experienced patientscompared with PI-naive patients. These authors sug-gest possible changes in regional body compositionindependent of PI therapy. In 1 study, 4 of 8 patientswho developed a buffalo hump had never receivedPIs.11 There is some speculation that changes in re-gional fat distribution have been occurring, even be-fore PI use, due to HIV-associated causes.

Many issues regarding HIV-associated lipodystro-phy syndrome remain unresolved. The underlyingmechanisms causing the metabolic and physiologicchanges, as well as the optimal treatment for HIV-associated lipodystrophy syndrome, need to be iden-tified. Although much of the research on the lipodys-trophy syndrome was performed with men, thesyndrome has been reported in both genders.20 Moreresearch is needed on lipodystrophy syndrome inHIV-infected women. Protease inhibitors continue tobe a major component of treatment for people withHIV and are under suspicion as a factor in the devel-opment of this syndrome. More data are needed toelucidate the relationship between HIV-associated li-podystrophy syndrome and PIs.

This report presents an unusual presentation ofantiretroviral-induced intraoral lipodystrophy. Thesignificant deposition of subcutaneous fat in thefloor of the mouth has not been reported previ-ously, but demonstrates another phenotype for thesyndrome of lipodystrophy in individuals treatedfor HIV infection with potent HAART. Differencesin the clinical pattern of presentation may havesignificance for patient management—it may bethat they have an unusual distribution of suscepti-ble receptors or enzymes present. A further under-standing of the molecular basis of lipodystrophy

2098 ORAL LIPOMATOSIS IN ANTIRETROVIRAL THERAPY

may be gained by an examination of the differencesin protein expression or mitochondrial markers inadipose tissue from different sites and in relation tothe phenotype. It seems unlikely that this pheno-type is a result of treatment factors alone, and it isprobable that host factors play a significant role.Such phenomenon warrant further investigations ata clinical and basic science level.

References1. Joint United Nations Program on HIV/AIDS: 2002 Statistics.

Available at: www.unaids.org. Accessed March 3, 20062. Greenspan JS, Greenspan D: The epidemiology of the oral

lesions of HIV infection in the developed world. Oral Dis 8:34,2002 (suppl 2)

3. Carpenter CA, Feinberg MT, Aubry WT, et al: Report of the NIHPanel to Define Principles of Therapy of HIV Infection. AnnIntern Med 128:1057, 1998

4. Mann M, Piazza-Hepp T, Koller E, et al: Unusual distributions ofbody fat in AIDS patients: A review of adverse events reportedto the Food and Drug Administration. AIDS Patient Care STDS13:287, 1999

5. Dong KL, Bausserman LL, Flynn MM, et al: Changes in bodyhabitus and serum lipid abnormalities in HIV-positive womenon highly active antiretroviral therapy (HAART). J Acquir Im-mune Defic Syndr 21:107, 1999

6. Williamson K, Reboli AC, Manders SM: Protease inhibitor-in-duced lipodystrophy. J Am Acad Dermatol 40: 635, 1999

7. Carr A, Samaras K, Chisholm DJ: Pathogenesis of HIV-1-pro-tease inhibitor-associated peripheral lipodystrophy, hyperlipi-daemia, and insulin resistance. Lancet 351:1881, 1998

8. Shaw AJ, McLean KA, Evans BA: Disorders of fat distribution inHIV infection. Int J STD AIDS 9:595, 1998

9. Carr A, Samaras K, Burton S, et al: A syndrome of peripherallipodystrophy, hyperlipidaemia and insulin resistance in pa-tients receiving HIV protease inhibitors. AIDS 12:F51, 1998

10. Yanovski JA, Miller K, Kino T, et al: Endocrine and metabolicevaluation of human immunodeficiency virus-infected patientswith evidence of protease inhibitor-associated lipodystrophy.J Clin Endocrinol Metab 84:925, 1999

11. Lo JC, Mulligan K, Tai VW, et al: Buffalo hump in men withHIV-1 infection. Lancet 351:867, 1998

12. Smith K, Germain M, Decker C, et al: Increased soft tissue inthe posterior cervical and upper back area of patients on HIV-1protease inhibitors. J Cutan Med Surg 3:211, 1999

13. Gervasoni C, Ridolfo AL, Trifiro G, et al: Redistribution of bodyfat in HIV-infected women undergoing combined antiretroviraltherapy. AIDS 13:465, 1998

14. Baker R, Kotler D, Carr A, et al: Altered body shape in HIVdisease: A side effect of therapy? AIDS Patient Care STDS13:395, 1999

15. Lichtenstein KA, Ward DJ, Moorman AC, et al: Clinical assess-ment of HIV-associated lipodystrophy in an ambulatory popu-lation. AIDS 15:1389, 2001

16. Kaul DR, Cinti SK, Carver PL, et al: HIV protease inhibitors:Advances in therapy and adverse reactions, including meta-bolic complications. Pharmacotherapy 19:281, 1999

17. Carr A, Samaras K, Thorisdottir A, et al: Diagnosis, prediction,and natural course of HIV-1 protease inhibitor-associated lipo-dystrophy, hyperlipidemia, and diabetes mellitus: A cohortstudy. Lancet 353:2093, 1999

18. Silva M, Skolnik PR, Gorbach SL, et al: The effect of proteaseinhibitors on weight and body composition in HIV-infectedpatients. AIDS 12:1645, 1998

19. Hadigan C, Miller K, Corcoran C, et al: Fasting hyperinsulin-emia and changes in regional body composition in humanimmunodeficiency virus-infected women. J Clin EndocrinolMetab 84:1932, 1999

20. Clark R, Niccolai L, Kissinger P, et al: Ethnic differences in bodyimage and perceptions among women infected with the hu-man immunodeficiency virus. J Am Dietetic Assoc 99:735,1999

J Oral Maxillofac Surg65:2099-2105, 2007

Marjolin’s Ulcer: A Review of theLiterature and Report of a Unique Patient

Treated With a CO2 LaserGregory P. Hatzis, DDS, MD,* and Richard Finn, DDS†

Marjolin’s ulcer is a well-recognized pathologic entitythat affects previously traumatized tissue. The causeand treatment of this neoplastic lesion remain contro-versial. We report a unique case of multiple Marjolin’sulcers (33) in a single patient, most of which affected

the face. To our knowledge, this is the first report ofthe use of a carbon dioxide (CO2) laser in the treat-ment of Marjolin’s ulcer.

Received from the Department of Surgery, Division of Oral and

Maxillofacial Surgery, University of Texas Southwestern Medical

Center Dallas, Parkland Memorial Hospital, Dallas, TX.

*Formerly, Chief Resident; Currently, Private Practice, Longview,

TX.

†Professor.

Address correspondence and reprint requests to Dr Hatzis:

Good Shepherd Medical Center, 700 East Marshall Ave, Longview,

TX 75601; e-mail: gregoryhatzis@yahoo.com

© 2007 American Association of Oral and Maxillofacial Surgeons

0278-2391/07/6510-0034$32.00/0

doi:10.1016/j.joms.2006.07.017

HATZIS AND FINN 2099