Herpesviridae-associated persistent mucocutaneous ulcers inacquired immunodeficiency syndrome

Vol. 81 No. 4 April 1996

II ORAL A N D MAXILLOFACIAL PATHOLOGY

Editor: Carl M. A l l e n

Herpesviridae-associated persistent mucocutaneous ulcers in acquired immunodeficiency syndrome A clinicopathologic study Catherine M. Flaitz, DDS, MS, a C. Mark Nichols, DDS, b and M. John Hicks, DDS, MS, PhD, MD, c Houston, Tex. DENTAL BRANCH, UNIVERSITYOF TEXAS-HOUSTONHEALTH SCIENCE CENTER, BERING SERVICE FOUNDATION DENTAL CLINIC, BAYLOR COLLEGE OF MEDICINE, AND TEXAS CHILDREN'S HOSPITAL Persistent mucocutaneous ulcers in AIDS represent a variety of disease entities. The purpose of this study was to characterize clinicopathologic features of persistent oral ulcers associated with cytomegalovirus and herpes simplex virus in AIDS. Forty-seven persons infected with HIV with persistent ulcers (mean, 2.4 ulcers/person) were included in this study. A biopsy specimen from a representative ulcer was taken from each patient. Hematoxylin-eosin, periodic acid-Schiff, cytomegalovirus, and herpes simplex virus immunocytochemical stains were performed on tissue sections. The most common sites of involvement were the buccal/labial mucosa (27%), tongue (25%), and gingiva (18%). Mean ulcer size was 1.8 cm with a mean duration of 5.6 weeks. The ulcerogenic viral agents were cytomegalovirus alone in 53% of cases, cytomegalovirus and herpes simplex virus coinfection in 28% of cases, and herpes simplex virus alone in 19% of cases. Treatment response to ganciclovir with or without topical steroids resulted in lesion resolution in the cytomegalovirus and cytomegalovirus/herpes simplex virus groups; however, recurrence/resistance was relatively high (23%). Herpes simplex virus/cytomegalovirus ulcers responded to oral acyclovir in combination with systemic ganciclovir. Increasing the oral acyclovir dosage resulted in resolution of herpes simplex virus--only ulcers in all but one case. Cytomegalovirus and herpes simplex virus are associated with persistent mucocutaneous ulcers in AIDS. These lesions responded to systemic antiviral therapy but are difficult to differentiate from other ulcerogenic diseases such as aphthous major, necrotizing stomatitis, and ulcerations not otherwise specified without biopsy and histopathologic examination. (ORAL SURGORAL MED ORAL PATHOLORAL RADIOL ENDOD 1996;81:433-41)

The m u c o u s membranes o f the oral cavity provide a means o f determining the overall health o f debilitated, i m m u n o c o m p r o m i s e d , and immunosuppressed persons. In persons who are HIV-seropositive, develop-

aAssociate Professor, Division of Oral Pathology, Department of Stornatology, Dental Branch, UTHHSC. bDirector of Bering Service Foundation Dental Clinic and Adjunct Associate Professor, Department of General Dentistry, Dental Branch, UTHHSC. CAssistant Professor, Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, and Adjunct Professor, Division of Pediatric Dentistry, UTHHSC. Received for publication July 11, 1995; returned for revision Aug. 15, 1995 and Oct. 17, 1995; accepted for publication Oct. 25, 1995. Copyright 9 1996 by Mosby-Year Book, Inc. 1079-2104/96/$5.00 + 0 7/14/70410

ment o f viral-induced lesions such as intraoral ulcers and hairy leukoplakia m a y represent the initial sign of H I V infection, herald the onset of A I D S , or indicate advancement o f H I V disease. 1-7 During t h e past decade, the herpesviridae has been shown to be responsible for a number o f oral conditions in H I V infection.l-7 The herpes virus family includes Epstein-Barr virus, herpes simplex (HSV) types I and I1, varicellazoster virus, cytomegalovirus (CMV), and human herpes viruses 6, 7, and 8. Within the herpesviridae, well-documented oral pathoses are produced by Epstein-Barr virus, H S V types ! and If, varicella-zoster virus, and CMV.1-7 The herpes family o f viruses has been associated with oral ulcerations in HIV-infected persons except for Epstein-Barr virus, which is associated with oral hairy leukoplakia. 1, 2 Mucosal ulcers 433

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April 1996 l a n e I. Demographics of study population Number of patients Mean age (range) Ethnicity White Hispanic African-American Men who have sex with men Heterosexual Injecting drug use Mean CD4 (range)

46 Men:l Women 37.4 years (21-55 years) 52% 28% 20% 83% 15% 2% 82/ram3 (7 to 200/mm3)

Therapeutic medications (at baseline) Antiretroviral medications AZT DDC DDI D4T Antiviral medications Acyclovir Ganciclovir Foscarnet Antifungal Fluconazole Nystatin Ketoconazole Anti-PCP Pentamidine Bactrim Chemo/radiotheraphy

39% 23% 3% 3% 32% 10% 3% 48% 29% 6% 29% 19% 3%

Opportunistic infections Candidiasis Pneumocystis carinii Cytomegalovirus Atypical mycobacteria Varicella Zoster Cryptococcus Hairy leukoplakia Toxoplasmosis

56% 26% 22% 13% 4% 4% 4% 2%

AIDS-associated malignancies Kaposi's sarcoma Lymphoma

11% 2%

Sexually transmitted diseases Herpes simplex type II Gonorrhea Syphilis Human papilloma vials Nongonococcal urethritis Hepatitis B virus No STDs reported

43% 33 % 20% 9% 4% 2% 37%

caused by HSV type I and II are seen within the oral cavities of 8% to 15% of HIV-seropositive persons.4, 8-10 These ulcers may be persistent and last for several weeks to months. With increasing interest in determining the cause, treatment, and prognostic significance of oral ulcers in HIV infection, it has become recognized that CMV is responsible for intraoral ulcers as well. 5-7, 1H6 More recently, iso-

lated cases of coinfection of oral ulcers with HSV and C M V have been reported in A I D S ) 7, 18 Persistent intraoral ulcers in HIV-seropositive patients are particularly challenging because these lesions may be caused by a number of etiologic agents and their presentations usually are quite atypical. Infectious agents (bacteria, fungi, viruses), therapeutic and prophylactic medications (interferon, ddC, foscarnet), malignancies (Kaposi's sarcoma, lymphoma, and squamous cell carcinoma), and unknown causes related to severe imrnunosuppression may be responsible for oral ulcerations. 3' 11-24 A biopsy of these persistent lesions may be necessary to determine if an infectious agent is responsible for the ulcer and for direction of therapeutic management. The purpose of this study was to Characterize the clinical and histopathologic features of oral ulcerations associated with two members of the herpesviri d a e - - C M V and H S V - - i n HIV-seropositive persons. In addition, treatment response of these ulcerative lesions to pharmaceutical management was evaluated.

MATERIAL AND METHODS Study population The study population consisted of 47 HIV-seropositive persons with a mean age of 37 years (range, 21 to 55 years) who had herpesviridae-associated chronic persistent ulcers proven by incisional or excisional biopsy (Table I). Inclusion in this clinicopathologic study was dependent on biopsy proven presence of herpesviridae infection (HSV or CMV) and did not represent consecutive chronic persistent oral ulcers. Chronic persistent ulcers were defined as intraoral ulcers either present for more than 2 weeks and not responding to empiric drug therapy or present for at least 2 weeks with a rapid increase in size or number. Incisional and excisional biopsies of representative persistent oral ulcers were obtained from each of the 47 HIV-seropositive subjects. Data about the lesions were recorded according to duration, signs, symptoms, and location.

Histopathologic examination of ulcers The biopsy tissue was fixed in 10% buffered formalin and processed for routine microscopic examination. In addition to hematoxylin-eosin (H-E) staining, the lesions were stained with periodic acid-Schiff (PAS) for fungi. Immunocytochemical studies were performed in all cases according to the manufacturer' s directions on deparaffinized sections with labeled streptavidin-biotin used to detect HSV I/II and CMV (Dako Corporation, Carpintera, Calif.) with appropriate positive and negative controls. After histopathologic diagnosis, the medications used to manage

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Fig. 1. Clinical appearances of Herpesviridae-induced chronic persistent mucocutaneous ulcers in HIV infection. A, Erosive ulcerative lesion involving maxillary mucobuccal fold; B, well-circumscribed, "punched-out" lesion involving lateral border and dorsum of tongue; C, deep ulcerative lesion involving retromolar gingiva and anterior tonsillar pillar; D, diffuse erosive lesion involving the posterior hard palate and soft palate. the patients were documented; the lesions were evaluated at periodic intervals until lesion resolution. RESULTS The demographic information about the 47 HIVseropositive persons included in this study is listed in Table I. The mean duration of these herpesviridae-induced chronic ulcers was approximately 6 weeks; several of the ulcers were present for 3 to 6 months without clinical resolution (Table II). Most of the lesions were multifocal in distribution with slightly over two persistent ulcers per subject. Oftentimes with gingival and hard palate involvement, periosteum became ex-

posed and resulted in sequestration of alveolar bone. Four distinct ulcerogenic patterns were observed clinically (Fig. 1). The first group of ulcers were moderately well-delineated, superficial ulcers with margins blending into the surrounding unaffected m u c o s a (Fig. 1,,4). The ulcer margins had a subtle feathery or floret pattern. The lesions typically were covered by a thin pseudomembrane. These ulcers tended to be more representative of early lesions and clinically resembled recurrent herpes simplex infection. The second group of lesions were well-delineated punched-out ulcers that lack indurated borders and have minimal inflammation (Fig. 1,B). The base of these ulcers were depressed, erythematous, and

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April 1996 l a n e II. Herpesviridae persistent ulcers in persons with AIDS Duration of lesions (mean) (range) Number of lesions Lesions per person (mean) (range) Maximum dimension (mean) (range) Ulcer sites Mucosa (labial/buccal) Tongue Gingiva Tonsillar pillars Palate Hard palate Soft palate Lip Floor of mouth Viral cause Cytomegalovirusalone Cytomegalovirusand herpes simplex virus Herpes simplex virus alone

5.6 weeks (2 to 40 weeks) 110 2.4 (1 to 12) 1.8 cm (0.4 to 8.0 cm) 27% 25% 18% 10% 10% (6%) (4%) 7% 2% 53% 28% 19%

often irregular, similar in appearance to aphthous major. Subepithelial fibrosis or scarring was a common feature after lesion resolution in this group: The third group of ulcers were diffuse often with jagged and irregular margins (Fig. 1,C). Frequently these ulcers were covered by thick tenacious pseudomembranes. Exposure of periosteum and bony sequestration were characteristic of this type of ulcer. These ulcers gave the clinical impression of " i n v a s i o n " or erosion into the adjacent bone and soft tissues. These lesions eventually healed with depressed scarring and had irregular redundant or rolled marginal tissue. Clinically, these lesions resembled necrotizing periodontitis or stomatitis. The final group of lesions were the least common and resembled drug-induced mucositis, such as that seen with lichenoid reactions and erythema multiforme (Fig. 1,D). Moderate to severe pain, lymphadenopathy, dysphagia, and weight loss were consistent findings among the four types of persistent herpesviridae-induced mucocutaneous lesions. The histopathologic appearance varied somewhat according to the clinical presentation of the ulcer. Typically, the mucosal ellipses were covered partially at their peripheries by stratified squamous epithelium exhibiting intracellular edema and ulceration (Figs. 2 and 3). The underlying submucosa consisted of chronically inflamed granulation tissue. The inflammatory infiltrate was composed of dense sheets of lymphocytes and macrophages with infrequent plasma cells interspersed. Neutrophils were usually confined

to the superficial ulcer bed. Eosinophils were present when there was evidence of degeneration of skeletal muscle bundles. The inflammatory infiltrate extended deep into the underlying ulcer bed and often resulted in degeneration of striated muscle and effacement of minor salivary glands. Viral cytopathic effects of CMV were observed by routine microscopic examination in the majority of ulcers (81%) with two distinct cell types identified (Table II, Fig. 2). Smudge cells were identified more frequently and appeared as large cells with oval to round basophilic nuclei and granular eosinophilic cytoplasm with or without cytoplasmic inclusions. Relatively large cells with classic " o w l e y e s " characterized by prominent central basophilic or amphophilic intranuclear inclusions surrounded by clear halos were the other cell type. The majority of CMVinduced cytopathic changes occurred in endothelial cells, perivascular stromal cells, or other stromal cells in the submucosa. Occasionally CMV-infected cells were found circulating within dilated vessels. Classic cytopathic changes of CMV could be identified when a minimum of six tissue sections were examined with most CMV-infected ulcers (87%). Immunocytochemical localization of CMV antigen was helpful in confirming the diagnosis when results of H-E stain were equivocal in 5 of the 38 CMV-infected ulcers. Occasional cells that resemble macrophages were immunoreactive for CMV; rare isolated surface epithelial cells were positive in only 2 of the 38 CMV-infected lesions. This phenomenon of apparently " n o r m a l " cells being infected with CMV is thought to represent occult infection typically seen in disseminated disease. 25 HSV infection alone was found in 19% of the ulcers (Table II, Fig. 3). The cytopathic effect of HSV on the surface epithelial cells was confirmed by immunocytochemistry. On routine staining, epithelial cells infected with HSV were characterized by acantholysis, nuclear clearing with peripheral margination of the chromatin, and ballooning degeneration with some of the HSV-infected epithelial cells being multinucleated. Coinfection with C M V and HSV was detected in 28% of the ulcers (Table II). Superficial candidiasis was detected by PAS staining with only 2 of the 47 lesions. Treatment response of these lesions was evaluated at weekly intervals. Before histopathologic diagnosis, most of the ulcers had been treated empirically with topical corticosteroids, oral acyclovir, or antibiotics without resolution. After microscopic diagnosis of C M V alone or CMV/HSV coinfection, most patients were treated with intravenous ganciclovir either alone (n = 14) or in combination with topical or systemic

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Fig. 2. Histopathologic appearance of CMV-induced chronic persistent mucocutaneous ulcers in HIV infection. A, Distinct border is present between area of ulceration and adjacent reactive squamous mucosa. Ulcer bed (A and B) is composed of granulation tissue with stromal and endothelial cells possessing typical nuclear and cytoplasmic CMV inclusions (arrows).

corticosteroids (n = 12), antibiotics (n---2), or acyclovir (n = 5). Foscarnet was administered in two additional patients. Lesions in two patients resolved with excisional biopsy. One patient responded to topical steroids initially but had a rapid recurrence. Three patients developed resistance to ganciclovir and were managed successfully with foscarnet. Most lesions responded dramatically within 5 days of ini-

fiation o f ganciclovir or foscarnet. Shortly after discontinuing ganciclovir, three patients had recurrences but responded to a second prolonged course of ganciclovir. Three patients either died o f AIDS-associated causes or were lost to follow-up. Overall, recurrence, resistance, or clinical nonresponsiveness to ganciclovir was observed in approximately 23% of the patients. W h e n H S V infection (n -- 9) was present

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Fig. 3. Histopathologic appearance of HSV-induced chronic persistent mucocutaneous ulcers in HIV infection. A, This ulcer shows necrotic debris and residual keratinocytes with HSV cytopathic effect (arrows); B, characteristic HSV nuclear inclusions are seen within squamous epithelial cells. Some of the HSV-infected cells are multinucleated.

alone, treatment with increased dosages of acyclovir alone (n -- 6) or in combination with topical steroids (n -- 2) resulted in resolution of the ulcers. One patient committed suicide before lesion resolution. DISCUSSION The utility of histopathologic evaluation in the management of persistent mucocutaneous lesions in

HIV-seropositive person is demonstrated with the findings from the present study. CMV and HSV may be detected by routine histopathologic examination in the majority of lesions. Confirmation of HSV or CMV infection may be carried out with immunocytochemical studies on paraffin-embedded tissue from the ulcers. A particularly interesting finding in this study was the relatively high percentage of CMV and HSV

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coinfected ulcers. Whereas the epithelial cells showed immunoreactivity for HSV, endothelial cells and stromal cells were immunoreactive for CMV. Crossreactivity between the immunocytochemical antibodies for CMV and HSV did not occur, which indicates that coinfection was present in over one quarter of the mucocutaneous ulcers in this study. HSV infection of epithelial cells without a concurrent CMV infection was less common than CMV infection of endothelial and stromal cells without a concurrent HSV infection. This may imply that the "stresses" initiated by the CMV-induced vasculitis may allow for reactivation of latent HSV infection or HSV reinfection of epithelial cells. 17, 18 The increased prevalence of CMV lesions also may be secondary to the fact that some of the lesions had been treated with oral acyclovir before biopsy and may have suppressed HSV expression. C M V reactivation or reinfection with medically induced immunosuppression in bone marrow and solid organ transplant patients is well known and ranges from at least 75% to 96% of transplant patients that are CMV seropositive. 6, 11, 25-29Likewise, there is serologic evidence that indicates that up to 80% of all adults and 94% of homosexual men between the ages of 18 to 29 years are CMV seropositive. 27-3~ With HIV infection, C M V seropositivity approaches 100% depending on HIV risk factors. 31, 32 In fact, it is quite common for HIV-infected homosexual men to exhibit chronic active C M V infection as evidenced by detection of CMV in urine, semen, throat washings, and saliva. 32-34 It is not surprising that the most common cause of life-threatening opportunistic infection in this group of patients is due to CMV. 25' 31, 35, 36 Autopsy data 35, 36 have demonstrated that about 90% of AIDS patients have active C M V infection; CMV-induced retinitis, pneumonitis, hepatitis, enteritis, and encephalitis are found quite frequently. In fact, CMV has been implicated as the primary or secondary cause of death in 25% of HIV-infected patients. 35, 36 Most CMV-infected oral lesions are ulcerative in nature and mimic herpetic, aphthoid, and periodontal lesions. 1,3qs Other unusual oral and maxillofacial presentations of C M V infection include osteomyelitis of the jaws, gingival hyperplasia, inflammatory hyperplasia of the oral mucosa, and concurrent infection in Kaposi's sarcoma. 6, 11, 12, 37-40 Treatment of oral lesions with CMV infection has varied in the past, but most commonly CMV infections are managed in most cases with intravenous ganciclovir or with foscarnet in refractory cases. 41-49 The response rate in this study is similar to other clinical studies that manage C M V retinitis or gastroenteritis with ganciclovir, an acyclovir analogue.

These studies have demonstrated initial rates of partial or complete response to ganciclovir in the 70% to 90% range. 4~ 44 In this uncontrolled study, a response rate of 77% was obtained for CMV and coinfected C M V / H S V ulcers when ganciclovir was used either alone or in combination with other agents. A significant problem with this antiviral agent is that drug therapy interruption m a y be necessary in up to 50% of patients as a result of myelosuppression. 32 In addition, CMV resistance or clinical nonresponsiveness to ganciclovir may occur with prolonged administration. 41-49 AS in the present study, foscarnet may be instituted in ganciclovir-resistant CMV infections. The pathogenesis of mucocutaneous ulcers in CMV infection is thought to be due to a localized vasculitis that results in surface ulceration and stromal proliferation, similar to that described for CMVinduced gastroenteritis and cutaneous disease. 6, 11, 19 The presence of CMV intranuclear and intracytoplasmic inclusions may represent hematogenous infection from a distant site and may indicate disseminated disease. Alternatively, the endothelial and stromal cells infected by C M V may represent occult disease that has become activated as a result of the advancing stage of disease in the immunocompromised host. Identification of CMV infection in persistent mucocutaneous lesions in H I V patients may provide for primary diagnosis of the early onset of systemic CMV infection or the detection of distant or disseminated C M V infection. Despite the uncertain pathogenesis and prognostic significance, CMV ulcers whether coinfected with HSV or not responded quite dramatically to ganciclovir therapy. Because coinfection with CMV and HSV does occur in persistent mucocutaneous ulcers in HIV, 17, 18 it is important to evaluate for both types of viral infections when one of these viral agents is identified either by routine microscopic or immunocytochemical means. I f CMV infection is not found, the offending agent may be HSV, which in the present study responded to increased levels of acyclovir therapy with or without steroid administration. Persistent ulcers in the HIV-seropositive population occur frequently and do not have characteristics that allow for clinical determination of the responsible etiologic agent. 3q8 Histopathologic examination of a representative lesion or lesions from an HIV-infected patient is of considerable importance in determining the causative agent and in directing therapy. The lack of specific clinical criteria for differentiating chronic oral herpetic ulcerations from major aphthous ulcerations and necrotizing stomatitis in the HIV-seropositive population further emphasizes the necessity for biopsy and histopathologic evaluation.

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April 1996 Whether CMV

i d e n t i f i c a t i o n in a n oral l e s i o n will

p l a y a r o l e in e a r l y d e t e c t i o n a n d i n t e r v e n t i o n in c l i n -

19.

i c a l l y o c c u l t C M V d i s s e m i n a t i o n to m a j o r o r g a n s y s t e m s in c a s e s in w h i c h C M V i n f e c t i o n a p p e a r s as an oral u l c e r o g e n i c p r o c e s s will d e p e n d on further clinicopathologic correlative investigations.

20. 21.

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Volume 81, Number 4 43. Emanuel D. Treatment of cytomegaloviral disease. Semin Hematol 1990;27:22-7. 44. Balfour HH. Management of cytomegalovirus disease with antiviral drugs. Rev Infect Dis 1990;12(suppl):S849-60. 45. Jacobson MA. Current management of cytomegalovirus disease in patients with AIDS. AIDS Res Hum Retroviruses 1994;10:917-24. 46. Wagstaff AJ, Bryson HM. Foscarnet: a reappraisal of its antiviral activity, pharmacokinetic properties, and therapeutic use in immunocompromised patients with viral infections. Drugs 1994;48:199-226. 47. Youle MS, Gazzard BG, Johnson MA, et al. Effects of high dose oral acyclovir on herpesvirus disease and survival in patients with advanced HIV disease. AIDS 1994;8:641-9.

48. Fletcher CV. Treatment of herpesvirus infection in HIVinfected individuals. Ann Pharmacol 1992;26:955-62. 49. Safrin S. Treatment of acyclovir-resistant herpes simplex virus infection in patients with AIDS. J Acquir Immune Defic Syndr 1992;5(suppl 1):$29-32.

Reprint requests: Dr. Catherine M. Flaitz Department of Stomatology Dental Branch University of Texas-Houston Health Science Center 6516 John Freeman Ave. Houston, TX 77030-3402