HIV-associated salivary gland disease: A review

HIV-associate review Marten Schi#dt, DDS, Dr Odont, Copenhagen, Denmark ORAL

AIDS

CENTER

FRANCISCO;

AND

DEPARTMENT

COPENHAGEN;

AND

DEPARTMENT OF ORAL

INSTITUTE

OF STOMATOLOGY,

UNIVERSlTY

MEDICINE

AND

ORAL

SURGERY,

OF PATHOLOGY

AND

MEDICINE,

ROYAL

OF CALIFORNIA, UNIVERSITY DENTAL

SAN

HOSPITAL, COLLEGE,

COPENHAGEN

Human immunodeficiency virus-associated salivary gland disease (HIV-SGD) is defined as the presence of xerostomia and/or swelling of the major salivary glands. It is common among children but uncommon among adults. HIV-SGD includes lymphoepithelial lesions and cysts involving the salivary gland tissue and/or intraglandular lymph nodes, and Sjogren’s syndrome-like conditions, diffuse interstitial lymphocytosis syndrome, and other reported lesions of the major salivary glands. This article reviews the terminology, prevalence, symptoms, clinical features, diagnostic procedures, histopathology, serology, natural history, treatment, and pathogenesis of HIV-SGD. (ORAL SURC ORAL MED ORAL P~THOL 1992;73:164-7)

A

number of lesions affecting the salivary glands have been noted in HIV infection. These lesions are characterized by enlargement of the major salivary glands, symptoms of dry mouth, or both. Only a few lesions are caused by neoplasms within the salivary glands. Thus most lesions are due to nonneoplastic swellings of the salivary gland tissue, the intraparotid lymph nodes, or both. This review deals only with the nonneoplastic lesions. Terminology. Table I shows the lesions affecting the salivary glands and salivary lymph nodes in HIV infection with the reported terminology. It is likely that many of the conditions are actually identical or that considerable overlap exists. The term “HIV-associated salivary gland disease” (HIV-SGD) will be used for designating HIV-infected persons with xerostomia, enlargement of one or more of the major salivary glands, or both. By this definition all patients iisted in Table I have HIV-SGD. Prevalence. Although the prevalence of salivary gland enlargement varies considerabiy among HIVinfected children (0% to 58%), it generally appears to be a common phenomenon. In adults, however, HIVSGD was not seen during the first years of the Supported

02. 7/12/31467

164

by National

Institutes

of Health

grant POl-DE07946

acquired immunodehciency syndrome (AIDS) epidemic and appears to be uncommon (Table II). Demographic data. The age distribution of patients with HIV-SGD falls into two groups: children born of HIV-infected mothers, and adults between 20 and 60 years of age. Of 64 reported cases,Iv4 8 1% were in the age group 25 to 50 years of age; 94% were men. A number of cases have been reported among blacks and a few among whites and Hispanics, but in most cases race was not stated. Among a total of 107 reported cases of HIV-SGD, 6 1% were in intravenous drug users and 39% were in homosexual men. Cases have occurred among transfusion recipients and hemophiliacs in San Francisco (Greenspan D, personal communication). It is thus likely that MIV-SGD can occur in all groups at risk for HIV infection. Symptoms. The main symptom is swelling of one or more of the major salivary glands, most often the parotids. Symptoms of xerostomia vary. None of 84 patients described as having benign lymphoepithelial lesions or cysts had xerostomia,‘, 5-8 whereas 30 of 33 patients (91%) described as having HIV-SGD,4 or Sjijgren’s syndrome-like conditions had dry mouth.9-12 Among the latter group symptoms of dry eyes and arthralgias are common. Clinicalfeatures. A review of 107 reported cases of HIV-SGD with salivary gland swelling revealed that the parotid was involved in 105 cases (98%) and the

HIV-associated

Volume 73 Number 2

salivary

gland disease

165

Table I. Reported lesions affecting salivary glands

submandibular gland in two cases (2%). The swellings were unilateral in 40% and bilateral in 60% of the cases.* The time of onset of salivary gland swelling varies from very early in the HIV infection (Centers for Disease Control stages II or III) to the symptomatic stage (IV), including AIDS. Similarly, the degree of immunodeficiency varies. Thus the peripheral CD4 cells varied from 37 t.o 800 cells/mm3, with a mean of 283 in one study.4 The CD8 cells are increased, contributing to a low CD4/CD8 ratio.2 Patisents with HIV-SGD may have extraglandular manifestations including lymphoid interstitial pneumonitis, gastritis, and hepatitis.2 Among children with HIV infection there is a significant association between parotid1 gland enlargement and the presence of lymphoid interstitial pneumonitis.13 Diagnostic plrocedures. In cases where the symptoms suggest a Sjiigren’s syndrome-like cond.ition a full “Sjogren workup” is suggested, including measurement of salivary flow rates; labial salivary gland biopsy and evaluation of focus score; eye examination for keratoconjunctivitis sicca; and serologic examination for antinuclear antibodies, rheumatoid factor, SS-A and SS-B antibodies. The salivary swelling should. be imaged by an adequate method such as computed tomographic (CT) scanning. In addition, the salivary swellings may be assessed by fine-needle aspiration (FNA) to exclude tumors (lymphomas, Kaposi’s sarcoma), although they may be difficult to interpret, and in selected cases a biopsy from the parotid gland may be indicated. Salivary characteristics. Patients with HIV-SGD and parotid gland swelling have significantly reduced stimulated parotid flow rates compared with HIV-seropositive control subjects.4 HIV cannot be cultured from the saliva of patients with HIV-SGD despite positive culture from the blood of the same patients.14 A preliminary study of the sialochemistry revealed increa.sed albumin and borderline increase of IgA, protein, and lysozyme in HIV-SGD.15 Thus the changes seen in HIV-SGD are similar to those seen in Sjogren’s syndrome but less pronounced. Imaging of salivary gland swelling. HIV-SGD has a characteristic appearance on CT and magnetic resonance imaging, where the salivary swellings occur as multicentric cysts or larger cysts ranging from 0.5 to 4.0 cm in diameter.6, l6 Because cystic lesions in the parotid glands were very rare im the pre-AIDS era, this is considered a new entity among radiologists. 16,I7 Other methods of imaging include ultrasound examination. However, in my opinion the

information obtained by this method is inferior to that from CT or magnetic resonance imaging. Sialography has rarely been used and may show acinar dilation as in Sjogren’s syndrome.‘* Fine-needle aspiration. FNA of the enlarged parotid glands reveals lymphocytic cells with or without epithelial cells3 In cases of lymphoepithelial cysts, a fluid can often be obtained. The main use of FNA is predominantly to exclude neoplasms, but findings should be interpreted with caution. Histopathology of labial salivary glands. Labial salivary gland biopsy of patients with HIV-SGD most often reveals a focal sialadenitis with a focus score of more than 1, as in Sjogren’s syndrome.4> 9, 12,ig The infiltrate is dominated by CD8+ cells, and the tissue CD4/CD8 ratio is 0.5 on average.4>t2 This is in contrast to the tissue CD4/CD8 ratio of 3 to 8 in classic Sjogren’s syndrome. Histopathology of major salivary glands. Superficial parotidectomies performed for cosmetic reasons on patients with swelling of the parotid glands have uniformly revealed lymphoepithelial lesions or cysts.* The lesion is histologically composed of a hyperplastic intraparotid lymph node, a lymphocytic infiltrate within the salivary gland tissue, or both. Epimyoepithelial islands are seen within the lymphoid tissue, and in some areas a cystic lumen is seen centrally. Larger cystic cavities lined with a nonkeratinized squamous epithelium and surrounded by lymphoid tissue showing germinal centers is typically seen. As in the labial salivary glands, the infiltrate in the parotid glands is dominated by CD8+ cells. Presently it is unknown to what degree changes in the minor salivary glands may reflect changes in the major glands.

“References

*References

l-10, 13, 14, 16-22, 25-29.

in HIV infection Neoplasms Kaposi’s sarcoma of parotid25 Lymphoma of parotid and/or intraparotid lymph nodes2’ Nonneoplastic changes Benign lymphoepithelial lesion’ Cystic lymphoid hyperplasia of parotid gland27 Diffuse infiltrative CD8 lymphocytosis syndrome* HIV-SGD4, I4 Lymphadenopathy of parotid glands32*I, ?2 Multicentric parotid cysts and cervical adenopathy17 Farotid swelling or enlargement’3, 18.28 Sicca complex9 Sjiigren’s syndrome-like illness’0 Sjogren’s syndrome19, 29

1, 3, 5-7, 10, 16, 17, 20, 21.

166

Schigidt

QRALSURGORAL

MED&UL?.~TH~L

February1992 Table

II. Prevalence of HIV-SGD

I Children

Adults

*Unpublished

presenting as swelling of major salivary glands Author (yv)

Location

I

Rubinsteinet al.‘j (1986) Colebunderset al.** (1988) Mastrucci et a1.30(1988) Goddartet a1.18(1990) Colebunderset a1.28(1988) Langfordet a1.3’(19X8) SchiQdtet al.* (1990)

New York

Kinshasa,Zaire Florida Brussels/Zaire Kinshasa Berlin Copenhagen

I

Prevalence i 96) 11/19 (58) O/40 (0) 5/24 (17) 4124 (17) O/284 (0) 2/260 (0.8) 21400 (0.5)

observations.

Serology. The serologic markers commonly present in Sjogren’s syndrome are usually absent in HIVSGD. These include antinuclear antibodies, rheumatoid factor, and SS-A and SS-B antibodies. Serum immunoglobulin levels are elevated.4 Natural history. The natural history of HIV-SGD is still poorly described. Although the salivary gland swellings may fluctuate, they are generally stable and !ong standing. In some cases they progress. It is suggested that HIV-SGD is associated with a rather favorable prognosis. Thus, among the 12 patients described by ltescu et al.,t2 an opportunistic infection developed in only one during 304 patient months of observation. Treatment. No definitive treatment is established for HIV-SGD. The clinical progression of the salivary gland swelling, which is probably most often associated with a lymphoepithelial cyst, may require surgical intervention for cosmetic reasons. The response to zidovudine and other antiviral agents such as acyclovir and phosphonoformate has yet to be explored. Symptoms of dry mouth should be treated as xerostomia associated with any other disease. This includes frequent dental examinations, good oral hygiene, stimulation of salivary flow by sugarless chewing gum or use of a saliva substitute when no functioning gland tissue remains, and topical use of fluoride. Pathogenesis. The pathogenesis of HIV-SGD is unknown. Histologically it is not possible to establish whether the lesion has primarily arisen from an intraparotid lymph node or from a lymphocytic infiltrate within the parotid gland tissue. Both mechanisms are likely to occur. Lymphadenopathy of the intraparotid lymph nodes is suggested by some authors,21, 22whereas others have suggested a Sjiigren’s syndrome-like condition arising as a lymphocytic infiltrate within the glandular tissue.” A viral etiology involving cytomegalovirus or Epstein-Barr virus was suggested, but studies performed so far have found no evidence of either virus. t4, 23 HIV has been detected occasionally by immunocytochemistry and in situ hybridization in the infiltrating lymphocytes of labial

salivary glands’” and parotid gland& 2oin HIV-SGD but has not been found in salivary acinar cells or duct epithelial cells. The significance of other viruses, including human herpesvirus type 6, which is excreted in the saliva,24 has not yet been elucidated. The fact that HIV-SGD only affects a small subset of HIV-infected persons suggests that certain factors are necessary for the condition to develop. Itescu et a1.12 found an increased prevalence of HLA-DR5 among a mostly black group of patients with HTVSGD. These findings await confirmation. The contributions and advice of Drs. T. E. Daniels, G. Dodd, D. Greenspan, and J. S. Greenspan are gratefully acknowledged. REFERENCES 1. Smith FB, Rajdeo H, Panesar N, Bhuta K, Stahl R. Benign

2.

3. 4.

5. 6. 7.

8. 9. 10. 11.

lymphoepithelial lesion of the parotid giand in intravenous drug users. Arch Path01 Lab Med 1988;112:742-5. Itescu S, Brancato LJ, Buxbaum J, et al. A diffuse infiltrative CD8 lymphocytosis syndrome in human immunodeficiency virus (HIV) infection: a host immune response associated with HLA-DR5. Ann Intern Med 1990;112:3-10. Shaha A, Thelmo W, Jaffe BM. Is parotid lymphadenopathy a new disease or part of AIDS? Am J Surg 1988;156:297-300. Schiadt M, Greenspan D, Daniels TE, et al. Parotid gland enlargement and xerostomia associated with labial sialadenitis in HIV-infected patients. J Autoimmun 1989;2:415-25. Kornstein MJ, Parker GA, Mills AS. lmmunohistology of the benign lymphoepithelial lesions in AIDS-related lymphadenopathy: a case report. Hum Pathol 198&;19:1359-61. Tunkel DE, Loury MC, Fox CH, Goins MA, Johns ME. Bilateral parotid enlargement in HIV-seropositive patients. Laryngoscope 1989;99:590-5. Finfer MD, Schinella RA, Rothstein SG, Persky MS. Cystic parotid lesions in patients at risk for the acquired immunodeficiency syndrome. Arch Otolaryngol Head Neck Surg 1988; 114:1290-4. Ramaswamy G, Saunders N, Belmonte H: Tchertkoff V. Benign lymphoepithelial cysts of the parotid gland in HIV-positive patients [Abstract]. Am J Clin Path01 !988;90:497. Couderc L-J, D’Agay M-F, Danon F, Harzic M, Brocheriou C, Clavel J-P. Sicca complex and infection with human immunodeficiency virus. Arch Intern Med 1987;147:898-901. Ulirsch RC, Jaffe ES. Sjogren’s syndrome-like illness associated with the acquired immunodeiiciency syndrome-related complex. Hum Path01 1987;18:1063-8. Haas C, Lowenstein W, Chargari A, Carnot F, Chamaret S, Durand H. Sialadenite lymphocytaire chronique apparent&e

Volume 73 Number 2

12.

13.

14. 15.

16.

17.

18.

19.

20.

21.

22.

au syndrome de Gougerot-Sjbgren revelatrice dune strologie VIII positive: une observation. Ann Med Intern 1989;140: 214-5. Itescu S, Brancato LJ, Winchester R. A sicca syndrome in HIV infection: association with HLA-DR.5 and CD8 lymphocytosis. Lancet 1989;2:466-8. Rubinstein A, Morecki B, Silverman M, et al. Pulmonary disease in children with acquired immune deficiency syndrome and AIDS-related complex. J Pediatr 1986;108:498-503. Schigidt M, Greenspan D, Levy JA, et al. What is the role of HIV in HIV-associated salivary gland disease? AIDS 1989; 3:819-22. Schiddt M, Atkinson J, Greenspan D, et al. Sialochemistry in HIV-associated1 salivary gland disease. Presented at Sixth International AIDS Conference; June 20-24, 1990; San Francisco. Holliday RA, Cohen WA, Schinella RA, et al. Benign lymphoepithelial parotid cysts and hyperplastic cervical adenopathy in AIDS-risk patients: a new CT appearance. Radiology 1988;168:439-44. Shugar JMA, Som PM, Jacobson AL, Ryan JR, Bernard P, Dickman SH. Multicentric parotid cysts and cervical adenopathy in AIDS patients: a newly recognized entity---CT and MR. manifestations. Laryngoscope 1988;98:772-5. Goddart D, Francois A, Ninane J, et al. Parotid gland abnormality in childlren seropositive for the human immunodeficiency virus (HIV). Pediatr Radio1 1990;20:355-7. Calabrese LH, Wilke WS, Perkins AD, Tubbs RR. Rheumatoid. arthritis complicated by infection with the human immunodeficiency virus and the development of SjBgren’s syndrome. Arthritis Rheum 1989;32:1453-7. Brunner JM, Cleary KR, Smith FB, Batsakis JG. Immunocytochemical identification of HIV (~24) antigen in parotid lymphoid lesions. J Laryngol Otol 1989;103:1063-6. Ioachim HL, Ryan JR, Blaugrund SM. Salivary gland lymph nodes: the site of lymphadenopathies and 1ymphoma.s associated with human immunodeficiency virus infection. Arch Path01 Lab Med 1988;112:1224-8. Poletti A, Manconi R, Volpe R, Carbone A. Study of AIDSrelated lymphadenopathy in the intraparotid and perimaxillary gland lymph nodes. J Oral Path01 1988;17:164-7.

HIV-associated

salivary gland disease

167

23. Veira J, Terry J, Astraloa J. Lymphoepithelial lesion: a manifestation of HIV infection lAbstract 71021. Presented at Fourth International Conference on AIDS; June 13-16, 1986; Stockholm. 24. Fox JD, Briggs M, Ward PA, Tedder RS. Human herpesvirus 6 in salivary glands. Lancet 1990;336:590-3. 25. Yeh C-K, Fox PC, Travis WD, Lane HC, Baum BJ. Kaposi’s sarcoma of the parotid gland in acquired immunodeficiency syndrome. ORAL SURC ORAL MED ORAL PATHOL 1989; 67:308-12.

26. Cleary KR, Batsakis JG. Lymphoepithelial cysts of the parotid region: a “new face” on an old lesion. Ann Otol Rhino1 Laryngo1 1990;99:162-4. 21. Vaillant JM, Chomette G, Talbi M, et al. Hyperplasie lymphoide kystique de la parotide en rapport avec unsyndrome d’immunodepression acouisb (HIV+). Rev Stomatol Chir Maxillofac 1989;90:136-41. 28. Colebunders R, Francis H, Mann JM, et al. Parotid swelling during human immunodeficiency virus infection. Arch Otolarvngol Head Neck Sure 1988:114:330-2. 29 Gordon J, Golbus J, Kurzdes ES. Chronic lymphadenopathy and Sjiigren’s syndrome in a homosexual man. N Engl J Med 1984;311:1441-2. 30 Mastrucci MT, Scott GB, Leggott PJ, Greenspan D, Greenspan JS. Oral manifestations of HIV infection in children [Abstract 75611. Presented at Fourth International Conference on AIDS; June 12-16, 1988; Stockholm. 31 Langford AA, Reichart P, Pohle HD. Oral manifestations associated with HIV-infection [Abstract 75781. Presented at Fourth International Conference on AIDS; June 12-16, 1988; Stockholm.

Reprint requests. M&ten Schiddt, DDS, Dr Odont Department of Oral Medicine and Oral Surgery Frederiksborg County Central Hospital 3400 Hille$d Denmark