ORIGINAL CONTRIBUTIONS
DIAGNOSTIC CHALLENGE
An impacted mandibular left third molar and pericoronitis in a human immunodeficiency virus–positive patient Julie Kazimiroff, DDS, MS; Kia Zeram, BS; Perry Cohen, MD; Jairo Bastidas, DMD; Victoria A. Muggia, MD; Jacqueline Polanco, DDS; Robert J. Kanas, DDS
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n 2008, a 21-year-old African American man sought treatment at the Department of Dentistry, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y., with a chief complaint of “sore gums.” His medical history was significant for human immunodeficiency virus (HIV)-1 infection, which had been diagnosed two years earlier. His risk factor for HIV acquisition was men having sex with men. At time of the examination, he recently had started antiretroviral therapy (ART), which consisted of atazanavir, ritonavir, abacavir and lamivudine. The clinical examination revealed an irregular, red, thickened gingiva surrounding the left mandibular second molar and impacted mandibular left third-molar operculum, retromolar pad and surface mucosa along the anterior ascending ramus (Figure 1). It measured 2.5 centimeters at its widest point. The gingiva appeared spongy, soft and superficially ulcerated. A panoramic radiograph revealed a horizontally impacted mandibular left third molar with a perifollicular space surrounding the crown that measured 0.7 cm (Figure 2). Pertinent laboratory results demonstrated a leukocyte count of 3,300 per microliter (58 percent neutrophils, 10 percent lymphocytes), a hemoglobin level of 13.9 grams per deciliter and a platelet count of 194,000 per μL. His cluster of differentiation (CD)4+ T-cell count was 177 cells per μL (normal range, 677-1,401 cells per μL) and HIV-1 RNA less than 75 copies per μL. When we screened the patient for herpes simplex virus (HSV) infection, the serologic results were positive for HSV-1 but not for HSV-2. One of the authors (J.P.) referred the patient to the hospital’s oral surgery department for removal of the impacted mandibular left third molar. The clinical and radiographic presentation initially suggested an inflammatory condition such as pericoronitis. An oral surgeon (J.B.) prescribed a regimen of amoxicillin (one 500-milligram tablet every eight hours for seven days), hydrocodone and acetaminophen (one tablet every four to six hours as
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ORIGINAL CONTRIBUTIONS
needed for pain), extra-strength ibuprofen and chlorhexidine rinses owing to heavy inflammation and pain, and he scheduled the patient to undergo removal of the mandibular left third molar under intravenous sedation. At the time of extraction, 12 days after initial presentation, the oral surgeon added the following note to the patient’s chart: “excised enlarged operculum secondary to pericoronitis.” The note implies that he recognized the extreme characteristics of this presentation and had the diligence to send the tissue for biopsy. The oral surgeon submitted the tissue biopsy specimen taken from the surface gingiva operculum covering the impacted mandibular left third molar to
Figure 1. Photograph showing a large, diffuse, red gingival thickening extending from the mandibular left second molar to the anterior ascending ramus with superficial ulceration and fibrin exudate.
the laboratory for histopathologic examination. The findings revealed that a spindle cell mass had replaced most of the submucosa with an intact overlying acanthotic squamous epithelium (Figure 3). The lesion was diffusely cellular, with organized fascicles of spindle cells and occasional storiform areas with compressed slitlike vascular spaces (Figure 4). The spindle cells were uniform and exhibited little cytologic atypia and only sporadic mitoses. The pathologist (P.C.) performed immunohistochemical analysis for CD31 marker (endothelial marker) and human herpesvirus-8 (HHV-8) latent nuclear antigen-1. The results of both stains were diffusely positive within the spindle cells of the neoplasm (Figures 5 and 6).
Figure 2. Radiograph showing an impacted mandibular left third molar with 0.7-centimeter pericoronal radiolucency.
Figure 3. Photomicrograph showing a cellular spindle-cell neoplasm replacing the submucosa of the gingiva overlying the third molar (hematoxylin-eosin stain, original magnification ×100).
HHV-8
Figure 4. Photomicrograph showing diffusely cellular neoplasm with organized fascicles of spindle cells and occasional storiform areas with compressed slitlike vascular spaces (hematoxylin-eosin stain, original magnification ×200). A few mitotic figures are present.
Figure 5. Photomicrograph showing diffuse immunopositivity within the spindle cells for cluster of differentiation 31 (CD31), an endothelial cell (vascular) marker (immunohistochemical staining, original magnification ×200).
A. pericoronitis secondary to an impacted tooth B. necrotizing ulcerative gingivitis C. intraoral Kaposi sarcoma
Figure 6. Photomicrograph showing diffuse immunopositivity within the spindle cells for human herpesvirus-8 (HHV-8) latent nuclear antigen-1 (immunohistochemical staining, original magnification ×200).
D. bacillary angiomatosis E. non-Hodgkin lymphoma
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THE DIAGNOSIS
Soon after the diagnosis of intraoral Kaposi sarcoma (KS) (resulting from immunodeficiency as a result of HIV infection) was established, the patient developed cervical and inguinal lymphadenopathy. Biopsy of a cervical lymph node demonstrated histopathologic findings consistent with KS. Despite what appeared to be a worsening in his clinical status and evidence of disseminated KS, the attending clinician (V.A.M.) decided to forgo chemotherapy and treat the patient with ART alone. The patient’s condition soon improved clinically, with marked improvement in his lymphadenopathy and, owing to his adherence to ART, no recurrence of the oral lesion. The patient’s CD4+ T-cell count improved from a low of 20 cells per μL to his press-time value of 303 cells per μL. At press time, he still was adhering to his current regimen of atazanavir, ritonavir, emtricitabine and tenofovir and had maintained an undetectable HIV viral load since the time of his KS diagnosis. His KS was in remission without the use of chemotherapy, and he remained healthy and active without evidence of disease. ORAL KAPOSI SARCOMA
The occurrence of oral KS in HIV-positive patients has been well documented. It is a tumor of endothelial cell origin, and HHV-8 is present within the neoplastic cells.1 It is estimated that 20 percent of patients with AIDS develop KS.2 However, in the ART era, reductions in KS incidence of between 19 and 93 percent have been reported among patients using ART when compared with patients not using ART.3 This primarily is because of the immune reconstitution that ART can trigger; patients receiving ART maintain a CD4+ T-cell count of 350 cells per μL or greater as a therapeutic goal. Therefore, intraoral KS is not as frequent an oral manifestation of HIV infection as it once was. Manifestations of KS. KS manifests as multiple skin or oral mucosal lesions in HIV-positive patients. The trunk, arms, head and neck are common sites; common intraoral sites include the palate, gingiva or tongue, but any mucosal site may be involved. The lesions appear as red, brown or purple macules, papules or nodules that rarely blanch with pressure. A biopsy is required to make a definitive diagnosis, because other lesions—such as those of bacillary angiomatosis and hemangiomas and lymphomas—may resemble those of KS. Although oral KS may appear at any intraoral mucosal site, including the gingiva, KS manifesting as pericoronitis is unusual. Other systemic diseases with clinical features similar to those of pericoronitis have been reported in immunocompetent people and include measles,4 infectious mononucleosis,5,6 acute lymphocytic leukemia,7 non-Hodgkin lymphoma8 and squamous cell
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carcinoma.9 Removing perifollicular tissue from the impacted extracted tooth and submitting it for histopathologic examination is a routine clinical practice. On the other hand, sampling and submitting a specimen of surface gingiva covering impacted third molars for biopsy is less frequent. When the covering gingiva involved with suspected pericoronitis demonstrates clinical abnormalities, a tissue biopsy is warranted. In this particular case, a gingival biopsy at the time of surgical removal of the third molar established the appropriate diagnosis without delay. KS has three clinical patterns, all of which share a common pathogenetic factor in HHV-8. dKaposi first described skin lesions ranging from red to brown to blue on the lower extremities of older men from the Mediterranean region in 1872.10 These were rare lesions that usually had a long, indolent clinical course; oral lesions were reported only infrequently. dAn endemic pattern in Africa is the second type; it affects primarily children and young adults and is equally prevalent in males and females. It too involves the skin of the extremities; oral lesions are reported only rarely. The clinical course is more aggressive than that of the classic, original type described by Kaposi, with earlier involvement of lymph nodes and visceral organs. dThe third type has been reported in patients with immunodeficiency, including that associated with organ transplants and with AIDS.11 In contrast to the first two types, in this type skin lesions are not limited to the extremities, and mucosal, visceral organ and lymph node involvement often appear early in the disease course. Patients with HIV-associated KS usually are young to middle-aged male adults. The clinical course is rather rapid and aggressive if untreated. KS has been seen less frequently in HIV-positive patients since the advent of ART.3 Diagnosing KS. Early lesions of KS may pose a diagnostic challenge.12 They may appear as single or multiple flat macules and may go unnoticed by the patient. Color changes from red to brown to blue have been described. Other conditions that mimic early forms of KS include ecchymosis, hemangioma, melanoma and pyogenic granuloma. Histologically, biopsy of early lesions may exhibit granulation tissue, extravasated red blood cells and slight spindle cell proliferation. Therefore, distinguishing an early KS lesion from a pyogenic granuloma may pose a diagnostic challenge.13 Clinicopathologic correlation is of utmost importance in establishing a diagnosis. Immunohistochemical studies also may be useful for diagnostic purposes. Antibodies to CD31, CD34 and factor VIII-related antigen will identify the proliferating spindle cells in KS as endothelial in origin. However,
ORIGINAL CONTRIBUTIONS
these markers do not always stain positive in KS lesions, and other vascular lesions may stain for these markers as well.14 Differential diagnosis of spindle cell neoplasms includes KS, angiosarcoma, leiomyosarcoma, melanoma and spindle-cell squamous cell carcinoma. Immunostaining for HHV-8 latent nuclear antigen-1 is beneficial in distinguishing these spindle cell neoplasms from KS, in addition to light-microscopic morphological features and other immunological markers such as cytokeratins, smooth muscle actin and human melanoma black 45 (Figure 6).15 Treating KS. Treatment of KS may vary depending on the level of immunodeficiency and presence of visceral involvement. With ART, KS may regress as the immune system reconstitutes. In cases that persist despite ART, single-agent chemotherapy such as vincristine, bleomycin, doxorubicin and paclitaxel has proved effective.16 Local management of oral lesions may be required because they may cause pain, bleeding, unpleasant esthetics or masticatory interference. Clinicians have removed lesions by means of scalpel incision or cryosurgery. Intralesional injection of oral lesions with vinblastine or sclerosing agents has been an effective adjunctive therapy.17 Electrosurgery and laser surgery should be avoided, because these procedures could aerosolize the viral particles within the neoplasm. DIFFERENTIAL DIAGNOSIS
Pericoronitis secondary to an impacted tooth. Pericoronitis is characterized by inflammation of the soft tissue surrounding the crown of an erupted or partially erupted tooth. The condition is associated most often with a partially impacted mandibular third molar in young patients aged 17 to 25 years. Signs and symptoms include pain, fever, localized swelling, trismus, red swollen soft tissue surrounding the tooth and purulent drainage.18 Antibiotics, pain medication and extraction of the affected tooth usually resolve the condition. Necrotizing ulcerative gingivitis. Necrotizing ulcerative gingivitis may occur at any age but frequently manifests in young and middle-aged adults. It has been reported in HIV-positive patients as an HIV-associated periodontal disease.19 Ulceration and necrosis of one or more interdental papillae with no loss of periodontal attachment characterize the condition. In contrast, necrotizing ulcerative periodontitis exhibits rapidly progressing loss of periodontal attachment. Bacillary angiomatosis. Bacillary angiomatosis is a bacterial infectious disease characterized by proliferative vascular lesions, seen mainly in HIV-positive patients with low CD4 counts and a Bartonella quintana or Bartonella henselae infection. B. henselae is well known to be the causative agent of cat-scratch disease. Oral lesions may appear as red to purple macules, papules or polypoid lesions of the gingiva or hard palate.20 These lesions may resemble KS, pyogenic granuloma and hemangiomas.
Tuberculosis. Oral tuberculosis is rare and occurs in less than 5 percent of patients with disseminated disease.21 Oral lesions may manifest as ulcerations, rough white plaques or exophytic masses. The tongue is the most common site, but the gingiva, buccal mucosa, floor of the mouth, lips and palate may be involved as well.22 A negative tuberculin skin test result does not rule out active tuberculosis and may be falsely negative in patients with advanced HIV. Therefore, demonstration of acidfast bacilli in tissue or by means of culture is necessary to confirm the diagnosis. Histoplasmosis. Histoplasma capsulatum is a fungus encountered worldwide; however, it is highly endemic in the Ohio and Mississippi river valleys.23 Patients with HIV and CD4+ T-cell counts of less than 200 per μL are at increased risk of dissemination of this fungus. Oral lesions may be a manifestation of disseminated disease. Oral lesions appear as a chronic ulcer with indurated borders involving any surface of the oral cavity.23 Recurrent HSV-1, recurrent varicella-zoster virus and cytomegalovirus infections. Recurrent HSV-1, recurrent varicella-zoster virus (VZV) and cytomegalovirus (CMV) all have been reported in HIV-positive patients.24-27 HSV-1 infection in HIV-positive patients usually is more widespread and persistent than that in patients not infected with HIV, lasting more than one month.24 Oral ulcerations occur in both keratinized and nonkeratinized oral mucosa. VZV reactivation in HIV-positive patients usually occurs in those younger than 40 years; in contrast, VZV reactivation in immunocompetent patients usually occurs in those well into their 60s. The distribution usually follows a single cutaneous dermatome and intraorally may follow a unilateral distribution of a branch of the trigeminal nerve. Necrosis and bone sequestration may occur in severe cases, leading to tooth loss.25 CMV disease may be a feature in HIVpositive patients, with CMV chorioretinitis the most common presentation. Oral CMV lesions are infrequent but have been reported as chronic mucosal ulcerations, with CMV histologic changes demonstrated in biopsy specimens from the ulcers.26,27 Oral squamous cell carcinoma. Oral squamous cell carcinoma (OSCC) has been reported in HIV-positive patients.2 However, the evidence documenting an increased risk of OSCC is, at best, equivocal. OSCC has been reported in younger people without other known risk factors for OSCC such as tobacco and alcohol use.28 An association between human papillomavirus (HPV) and OSCC in HIV-positive participants suggests that HPV-16 plays a role, especially in the tonsillar area.2 Clinical lesions appear as white, red or mixed red and white plaques, nodules or ulcers in the tongue, gingiva, tonsils or palate. Lesions in HIV-positive patients tend to be more advanced at time of diagnosis and are associated with a lower rate of survival. Non-Hodgkin lymphoma. Non-Hodgkin lymphoma
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may simulate periodontal disease, causing gingival thickening as well as color changes, ulceration and necrosis of the gingiva, palate and alveolar mucosa.2 The majority of HIV-associated lymphomas are aggressive Burkitt lymphomas, diffuse large B-cell lymphomas or immunoblastic lymphomas associated with Epstein-Barr virus.29 Unlike with non-Hodgkin lymphoma, ART has been effective in preventing oral candidiasis, oral hairy leukoplakia and KS.30 CONCLUSIONS
A case of KS in a young HIV-positive man that manifested clinically as pericoronitis was diagnosed successfully because a clinician performed a gingival biopsy when removing the impacted mandibular left third molar. A clinician who observes abnormal clinical changes in the gingiva overlying a patient’s impacted third molar should consider performing a biopsy of the affected tissue. This practice will prevent a delay in diagnosis and appropriate therapy for patients. ■ doi:10.14219.jada.2014.71 Dr. Kazimiroff is the director of community dentistry, Department of Dentistry, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Mr. Zeram is a doctoral candidate, College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah. Dr. Cohen is a pathologist, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Dr. Bastidas is the deputy director, Oral and Maxillofacial Surgery Residency Program, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Dr. Muggia is the attending physician, Section of Infectious Disease, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Dr. Polanco is the attending dentist, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Dr. Kanas was an associate professor, Oral and Maxillofacial Pathology, College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah, when this article was written. He now is a staff dentist, Michigan Community Dental Clinics, Port Huron. Address correspondence to Dr. Kanas at [email protected]. Disclosure. None of the authors reported any disclosures. This work was supported in part by grant H97HA075 from the Health Resource Services Administration, U.S. Department of Health and Human Services, Rockville, Md. Information on the case described in this article was presented in part as a case report at the Western Society of Teachers of Oral Pathology meeting in Kona, Hawaii, Oct. 28-30, 2012. Diagnostic Challenge is published in collaboration with the American Academy of Oral and Maxillofacial Pathology and the American Academy of Oral Medicine. 1. Mesri EA. Inflammatory reactivation and angiogenicity of Kaposi’s sarcoma-associated herpesvirus/HHV8: a missing link in the pathogenesis of acquired immunodeficiency syndrome-associated Kaposi’s sarcoma. Blood 1999;93(12):4031-4033. 2. Epstein JB, Cabay RJ, Glick M. Oral malignancies in HIV disease: changes in disease presentation, increasing understanding of molecular pathogenesis, and current management. Oral Surg Oral Med Oral Pathol
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Oral Radiol Endod 2005;100(5):571-578. 3. Semeere AS, Busakhala N, Martin JN. Impact of antiretroviral therapy on the incidence of Kaposi’s sarcoma in resource-rich and resourcelimited settings. Curr Opin Oncol 2012;24(5):522-530. 4. Katz J, Guelmann M, Stavropolous F, Heft M. Gingival and other oral manifestations in measles virus infection. J Clin Periodontol 2003;30(7):665-668. 5. Kadesh JB, Albers DD. Infectious mononucleosis first manifest by mandibular pericoronitis: report of case. Gen Dent 1981;29(5):428-429. 6. Benoliel R, Katz J. Infectious mononucleosis first manifest by pericoronitis: two case reports. Ann Dent 1989;48(1):30-32. 7. Aronovich S, Connolly TW. Pericoronitis as an initial manifestation of acute lymphoblastic leukemia: a case report. J Oral Maxillofac Surg 2008;66(4):804-808. 8. Dhanrajani PJ, Swaify GA, Khateery SM. Malignant lymphoma presenting as pericoronitis: a case report. Int J Oral Maxillofac Surg 1992;21(5):295-296. 9. Sleeman DJ, Thomas S, Telfer M, Irvine GH. Intra-oral carcinoma simulating benign oral disease. Br Dent J 1992;173(9):312-313. 10. Tornesello ML, Biryahwaho B, Downing R, et al. Human herpesvirus type 8 variants circulating in Europe, Africa and North America in classic, endemic and epidemic Kaposi’s sarcoma lesions during pre-AIDS and AIDS era. Virology 2010;398(2):280-289. 11. Hosseini-Moghaddam SM, Soleimanirahbar A, Mazzulli T, Rotstein C, Husain S. Post renal transplantation Kaposi’s sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy. Transpl Infect Dis 2012;14(4):338-345. 12. Dictor M, Rambech E, Way D, Witte M, Bendsoe N. Human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus) DNA in Kaposi’s sarcoma lesions, AIDS Kaposi’s sarcoma cell lines, endothelial Kaposi’s sarcoma simulators, and the skin of immunosuppressed patients. Am J Pathol 1996;148(6):2009-2016. 13. Ramirez-Amador V, Martinez-Mata G, Gonzalez-Ramirez I, AnayaSaavedra G, de Almeida OP. Clinical, histological and immunohistochemical findings in oral Kaposi’s sarcoma in a series of Mexican AIDS patients: comparative study. J Oral Pathol Med 2009;38(4):328-333. 14. Rosado FG, Itani DM, Coffin CM, Cates JM. Utility of immunohistochemical staining with FLI1, D2-40, CD31, and CD34 in the diagnosis of acquired immunodeficiency syndrome-related and non-acquired immunodeficiency syndrome-related Kaposi sarcoma. Arch Pathol Lab Med 2012;136(3):301-304. 15. Radu O, Pantanowitz L. Kaposi sarcoma. Arch Pathol Lab Med 2013;137(2):289-294. 16. Fatahzadeh M, Schwartz RA. Oral Kaposi’s sarcoma: a review and update. Int J Dermatol 2013;52(6):666-672. 17. Baccaglini L, Atkinson JC, Patton LL, Glick M, Ficarra G, Peterson DE. Management of oral lesions in HIV-positive patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(suppl):S50.e1-S50.e23. 18. McNutt M, Partrick M, Shugars DA, Phillips C, White RP Jr. Impact of symptomatic pericoronitis on health-related quality of life. J Oral Maxillofac Surg 2008;66(12):2482-2487. doi:10.1016/j.joms.2008.07.005. 19. Umadevi M, Adeyemi O, Patel M, Reichart PA, Robinson PG. (B2) Periodontal diseases and other bacterial infections. Adv Dent Res 2006;19(1):139-145. 20. Lopez de Blanc S, Sambuelli R, Femopase F, et al. Bacillary angiomatosis affecting the oral cavity: report of two cases and review. J Oral Pathol Med 2000;29(2):91-96. 21. Samaranayake P. Re-emergence of tuberculosis and its variants: implications for dentistry. Int Dent J 2002;52(5):330-336. 22. Piluso S, Ficarra G, Lucatorto FM, et al. Cause of oral ulcers in HIVinfected patients: a study of 19 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82(2):166-172. 23. Chinn H, Chernoff DN, Migliorati CA, Silverman S Jr, Green TL. Oral histoplasmosis in HIV-infected patients: report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79(6):710-714. 24. Arduino PG, Porter SR. Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management. Oral Dis 2006;12(3): 254-270. 25. Feller L, Wood NH, Raubenheimer EJ, Meyerov R, Lemmer J. Alveolar bone necrosis and spontaneous tooth exfoliation in an HIVseropositive subject with herpes zoster. SADJ 2008;63(2):106-110. 26. Kanas RJ, Jensen JL, Abrams AM, Wuerker RB. Oral mucosal cytomegalovirus as a manifestation of the acquired immune deficiency
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syndrome. Oral Surg Oral Med Oral Pathol 1987;64(2):183-189. 27. Delgado WA, Almeida OP, Vargas PA, Leon JE. Oral ulcers in HIV-positive Peruvian patients: an immunohistochemical and in situ hybridization study. J Oral Pathol Med 2009;38(1):120-125. 28. Anil S, Beena VT, Nair RG. Squamous cell carcinoma of the gingiva in an HIV-positive patient: a case report. Dent Update 1996;23(10): 424-425. 29. Nador RG, Chadburn A, Gundappa G, Cesarman E, Said JW,
Knowles DM. Human immunodeficiency virus (HIV)-associated polymorphic lymphoproliferative disorders. Am J Surg Pathol 2003;27(3): 293-302. 30. Patton LL. Sensitivity, specificity, and positive predictive value of oral opportunistic infections in adults with HIV/AIDS as markers of immune suppression and viral burden. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90(2):182-188.
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DIAGNOSTIC CHALLENGE
An impacted mandibular left third molar and pericoronitis in a human immunodeficiency virus–positive patient Julie Kazimiroff, DDS, MS; Kia Zeram, BS; Perry Cohen, MD; Jairo Bastidas, DMD; Victoria A. Muggia, MD; Jacqueline Polanco, DDS; Robert J. Kanas, DDS
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THE CHALLENGE
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n 2008, a 21-year-old African American man sought treatment at the Department of Dentistry, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y., with a chief complaint of “sore gums.” His medical history was significant for human immunodeficiency virus (HIV)-1 infection, which had been diagnosed two years earlier. His risk factor for HIV acquisition was men having sex with men. At time of the examination, he recently had started antiretroviral therapy (ART), which consisted of atazanavir, ritonavir, abacavir and lamivudine. The clinical examination revealed an irregular, red, thickened gingiva surrounding the left mandibular second molar and impacted mandibular left third-molar operculum, retromolar pad and surface mucosa along the anterior ascending ramus (Figure 1). It measured 2.5 centimeters at its widest point. The gingiva appeared spongy, soft and superficially ulcerated. A panoramic radiograph revealed a horizontally impacted mandibular left third molar with a perifollicular space surrounding the crown that measured 0.7 cm (Figure 2). Pertinent laboratory results demonstrated a leukocyte count of 3,300 per microliter (58 percent neutrophils, 10 percent lymphocytes), a hemoglobin level of 13.9 grams per deciliter and a platelet count of 194,000 per μL. His cluster of differentiation (CD)4+ T-cell count was 177 cells per μL (normal range, 677-1,401 cells per μL) and HIV-1 RNA less than 75 copies per μL. When we screened the patient for herpes simplex virus (HSV) infection, the serologic results were positive for HSV-1 but not for HSV-2. One of the authors (J.P.) referred the patient to the hospital’s oral surgery department for removal of the impacted mandibular left third molar. The clinical and radiographic presentation initially suggested an inflammatory condition such as pericoronitis. An oral surgeon (J.B.) prescribed a regimen of amoxicillin (one 500-milligram tablet every eight hours for seven days), hydrocodone and acetaminophen (one tablet every four to six hours as
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needed for pain), extra-strength ibuprofen and chlorhexidine rinses owing to heavy inflammation and pain, and he scheduled the patient to undergo removal of the mandibular left third molar under intravenous sedation. At the time of extraction, 12 days after initial presentation, the oral surgeon added the following note to the patient’s chart: “excised enlarged operculum secondary to pericoronitis.” The note implies that he recognized the extreme characteristics of this presentation and had the diligence to send the tissue for biopsy. The oral surgeon submitted the tissue biopsy specimen taken from the surface gingiva operculum covering the impacted mandibular left third molar to
Figure 1. Photograph showing a large, diffuse, red gingival thickening extending from the mandibular left second molar to the anterior ascending ramus with superficial ulceration and fibrin exudate.
the laboratory for histopathologic examination. The findings revealed that a spindle cell mass had replaced most of the submucosa with an intact overlying acanthotic squamous epithelium (Figure 3). The lesion was diffusely cellular, with organized fascicles of spindle cells and occasional storiform areas with compressed slitlike vascular spaces (Figure 4). The spindle cells were uniform and exhibited little cytologic atypia and only sporadic mitoses. The pathologist (P.C.) performed immunohistochemical analysis for CD31 marker (endothelial marker) and human herpesvirus-8 (HHV-8) latent nuclear antigen-1. The results of both stains were diffusely positive within the spindle cells of the neoplasm (Figures 5 and 6).
Figure 2. Radiograph showing an impacted mandibular left third molar with 0.7-centimeter pericoronal radiolucency.
Figure 3. Photomicrograph showing a cellular spindle-cell neoplasm replacing the submucosa of the gingiva overlying the third molar (hematoxylin-eosin stain, original magnification ×100).
HHV-8
Figure 4. Photomicrograph showing diffusely cellular neoplasm with organized fascicles of spindle cells and occasional storiform areas with compressed slitlike vascular spaces (hematoxylin-eosin stain, original magnification ×200). A few mitotic figures are present.
Figure 5. Photomicrograph showing diffuse immunopositivity within the spindle cells for cluster of differentiation 31 (CD31), an endothelial cell (vascular) marker (immunohistochemical staining, original magnification ×200).
A. pericoronitis secondary to an impacted tooth B. necrotizing ulcerative gingivitis C. intraoral Kaposi sarcoma
Figure 6. Photomicrograph showing diffuse immunopositivity within the spindle cells for human herpesvirus-8 (HHV-8) latent nuclear antigen-1 (immunohistochemical staining, original magnification ×200).
D. bacillary angiomatosis E. non-Hodgkin lymphoma
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ORIGINAL CONTRIBUTIONS
THE DIAGNOSIS
Soon after the diagnosis of intraoral Kaposi sarcoma (KS) (resulting from immunodeficiency as a result of HIV infection) was established, the patient developed cervical and inguinal lymphadenopathy. Biopsy of a cervical lymph node demonstrated histopathologic findings consistent with KS. Despite what appeared to be a worsening in his clinical status and evidence of disseminated KS, the attending clinician (V.A.M.) decided to forgo chemotherapy and treat the patient with ART alone. The patient’s condition soon improved clinically, with marked improvement in his lymphadenopathy and, owing to his adherence to ART, no recurrence of the oral lesion. The patient’s CD4+ T-cell count improved from a low of 20 cells per μL to his press-time value of 303 cells per μL. At press time, he still was adhering to his current regimen of atazanavir, ritonavir, emtricitabine and tenofovir and had maintained an undetectable HIV viral load since the time of his KS diagnosis. His KS was in remission without the use of chemotherapy, and he remained healthy and active without evidence of disease. ORAL KAPOSI SARCOMA
The occurrence of oral KS in HIV-positive patients has been well documented. It is a tumor of endothelial cell origin, and HHV-8 is present within the neoplastic cells.1 It is estimated that 20 percent of patients with AIDS develop KS.2 However, in the ART era, reductions in KS incidence of between 19 and 93 percent have been reported among patients using ART when compared with patients not using ART.3 This primarily is because of the immune reconstitution that ART can trigger; patients receiving ART maintain a CD4+ T-cell count of 350 cells per μL or greater as a therapeutic goal. Therefore, intraoral KS is not as frequent an oral manifestation of HIV infection as it once was. Manifestations of KS. KS manifests as multiple skin or oral mucosal lesions in HIV-positive patients. The trunk, arms, head and neck are common sites; common intraoral sites include the palate, gingiva or tongue, but any mucosal site may be involved. The lesions appear as red, brown or purple macules, papules or nodules that rarely blanch with pressure. A biopsy is required to make a definitive diagnosis, because other lesions—such as those of bacillary angiomatosis and hemangiomas and lymphomas—may resemble those of KS. Although oral KS may appear at any intraoral mucosal site, including the gingiva, KS manifesting as pericoronitis is unusual. Other systemic diseases with clinical features similar to those of pericoronitis have been reported in immunocompetent people and include measles,4 infectious mononucleosis,5,6 acute lymphocytic leukemia,7 non-Hodgkin lymphoma8 and squamous cell
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carcinoma.9 Removing perifollicular tissue from the impacted extracted tooth and submitting it for histopathologic examination is a routine clinical practice. On the other hand, sampling and submitting a specimen of surface gingiva covering impacted third molars for biopsy is less frequent. When the covering gingiva involved with suspected pericoronitis demonstrates clinical abnormalities, a tissue biopsy is warranted. In this particular case, a gingival biopsy at the time of surgical removal of the third molar established the appropriate diagnosis without delay. KS has three clinical patterns, all of which share a common pathogenetic factor in HHV-8. dKaposi first described skin lesions ranging from red to brown to blue on the lower extremities of older men from the Mediterranean region in 1872.10 These were rare lesions that usually had a long, indolent clinical course; oral lesions were reported only infrequently. dAn endemic pattern in Africa is the second type; it affects primarily children and young adults and is equally prevalent in males and females. It too involves the skin of the extremities; oral lesions are reported only rarely. The clinical course is more aggressive than that of the classic, original type described by Kaposi, with earlier involvement of lymph nodes and visceral organs. dThe third type has been reported in patients with immunodeficiency, including that associated with organ transplants and with AIDS.11 In contrast to the first two types, in this type skin lesions are not limited to the extremities, and mucosal, visceral organ and lymph node involvement often appear early in the disease course. Patients with HIV-associated KS usually are young to middle-aged male adults. The clinical course is rather rapid and aggressive if untreated. KS has been seen less frequently in HIV-positive patients since the advent of ART.3 Diagnosing KS. Early lesions of KS may pose a diagnostic challenge.12 They may appear as single or multiple flat macules and may go unnoticed by the patient. Color changes from red to brown to blue have been described. Other conditions that mimic early forms of KS include ecchymosis, hemangioma, melanoma and pyogenic granuloma. Histologically, biopsy of early lesions may exhibit granulation tissue, extravasated red blood cells and slight spindle cell proliferation. Therefore, distinguishing an early KS lesion from a pyogenic granuloma may pose a diagnostic challenge.13 Clinicopathologic correlation is of utmost importance in establishing a diagnosis. Immunohistochemical studies also may be useful for diagnostic purposes. Antibodies to CD31, CD34 and factor VIII-related antigen will identify the proliferating spindle cells in KS as endothelial in origin. However,
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these markers do not always stain positive in KS lesions, and other vascular lesions may stain for these markers as well.14 Differential diagnosis of spindle cell neoplasms includes KS, angiosarcoma, leiomyosarcoma, melanoma and spindle-cell squamous cell carcinoma. Immunostaining for HHV-8 latent nuclear antigen-1 is beneficial in distinguishing these spindle cell neoplasms from KS, in addition to light-microscopic morphological features and other immunological markers such as cytokeratins, smooth muscle actin and human melanoma black 45 (Figure 6).15 Treating KS. Treatment of KS may vary depending on the level of immunodeficiency and presence of visceral involvement. With ART, KS may regress as the immune system reconstitutes. In cases that persist despite ART, single-agent chemotherapy such as vincristine, bleomycin, doxorubicin and paclitaxel has proved effective.16 Local management of oral lesions may be required because they may cause pain, bleeding, unpleasant esthetics or masticatory interference. Clinicians have removed lesions by means of scalpel incision or cryosurgery. Intralesional injection of oral lesions with vinblastine or sclerosing agents has been an effective adjunctive therapy.17 Electrosurgery and laser surgery should be avoided, because these procedures could aerosolize the viral particles within the neoplasm. DIFFERENTIAL DIAGNOSIS
Pericoronitis secondary to an impacted tooth. Pericoronitis is characterized by inflammation of the soft tissue surrounding the crown of an erupted or partially erupted tooth. The condition is associated most often with a partially impacted mandibular third molar in young patients aged 17 to 25 years. Signs and symptoms include pain, fever, localized swelling, trismus, red swollen soft tissue surrounding the tooth and purulent drainage.18 Antibiotics, pain medication and extraction of the affected tooth usually resolve the condition. Necrotizing ulcerative gingivitis. Necrotizing ulcerative gingivitis may occur at any age but frequently manifests in young and middle-aged adults. It has been reported in HIV-positive patients as an HIV-associated periodontal disease.19 Ulceration and necrosis of one or more interdental papillae with no loss of periodontal attachment characterize the condition. In contrast, necrotizing ulcerative periodontitis exhibits rapidly progressing loss of periodontal attachment. Bacillary angiomatosis. Bacillary angiomatosis is a bacterial infectious disease characterized by proliferative vascular lesions, seen mainly in HIV-positive patients with low CD4 counts and a Bartonella quintana or Bartonella henselae infection. B. henselae is well known to be the causative agent of cat-scratch disease. Oral lesions may appear as red to purple macules, papules or polypoid lesions of the gingiva or hard palate.20 These lesions may resemble KS, pyogenic granuloma and hemangiomas.
Tuberculosis. Oral tuberculosis is rare and occurs in less than 5 percent of patients with disseminated disease.21 Oral lesions may manifest as ulcerations, rough white plaques or exophytic masses. The tongue is the most common site, but the gingiva, buccal mucosa, floor of the mouth, lips and palate may be involved as well.22 A negative tuberculin skin test result does not rule out active tuberculosis and may be falsely negative in patients with advanced HIV. Therefore, demonstration of acidfast bacilli in tissue or by means of culture is necessary to confirm the diagnosis. Histoplasmosis. Histoplasma capsulatum is a fungus encountered worldwide; however, it is highly endemic in the Ohio and Mississippi river valleys.23 Patients with HIV and CD4+ T-cell counts of less than 200 per μL are at increased risk of dissemination of this fungus. Oral lesions may be a manifestation of disseminated disease. Oral lesions appear as a chronic ulcer with indurated borders involving any surface of the oral cavity.23 Recurrent HSV-1, recurrent varicella-zoster virus and cytomegalovirus infections. Recurrent HSV-1, recurrent varicella-zoster virus (VZV) and cytomegalovirus (CMV) all have been reported in HIV-positive patients.24-27 HSV-1 infection in HIV-positive patients usually is more widespread and persistent than that in patients not infected with HIV, lasting more than one month.24 Oral ulcerations occur in both keratinized and nonkeratinized oral mucosa. VZV reactivation in HIV-positive patients usually occurs in those younger than 40 years; in contrast, VZV reactivation in immunocompetent patients usually occurs in those well into their 60s. The distribution usually follows a single cutaneous dermatome and intraorally may follow a unilateral distribution of a branch of the trigeminal nerve. Necrosis and bone sequestration may occur in severe cases, leading to tooth loss.25 CMV disease may be a feature in HIVpositive patients, with CMV chorioretinitis the most common presentation. Oral CMV lesions are infrequent but have been reported as chronic mucosal ulcerations, with CMV histologic changes demonstrated in biopsy specimens from the ulcers.26,27 Oral squamous cell carcinoma. Oral squamous cell carcinoma (OSCC) has been reported in HIV-positive patients.2 However, the evidence documenting an increased risk of OSCC is, at best, equivocal. OSCC has been reported in younger people without other known risk factors for OSCC such as tobacco and alcohol use.28 An association between human papillomavirus (HPV) and OSCC in HIV-positive participants suggests that HPV-16 plays a role, especially in the tonsillar area.2 Clinical lesions appear as white, red or mixed red and white plaques, nodules or ulcers in the tongue, gingiva, tonsils or palate. Lesions in HIV-positive patients tend to be more advanced at time of diagnosis and are associated with a lower rate of survival. Non-Hodgkin lymphoma. Non-Hodgkin lymphoma
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may simulate periodontal disease, causing gingival thickening as well as color changes, ulceration and necrosis of the gingiva, palate and alveolar mucosa.2 The majority of HIV-associated lymphomas are aggressive Burkitt lymphomas, diffuse large B-cell lymphomas or immunoblastic lymphomas associated with Epstein-Barr virus.29 Unlike with non-Hodgkin lymphoma, ART has been effective in preventing oral candidiasis, oral hairy leukoplakia and KS.30 CONCLUSIONS
A case of KS in a young HIV-positive man that manifested clinically as pericoronitis was diagnosed successfully because a clinician performed a gingival biopsy when removing the impacted mandibular left third molar. A clinician who observes abnormal clinical changes in the gingiva overlying a patient’s impacted third molar should consider performing a biopsy of the affected tissue. This practice will prevent a delay in diagnosis and appropriate therapy for patients. ■ doi:10.14219.jada.2014.71 Dr. Kazimiroff is the director of community dentistry, Department of Dentistry, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Mr. Zeram is a doctoral candidate, College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah. Dr. Cohen is a pathologist, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Dr. Bastidas is the deputy director, Oral and Maxillofacial Surgery Residency Program, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Dr. Muggia is the attending physician, Section of Infectious Disease, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Dr. Polanco is the attending dentist, Montefiore Medical Center, The University Hospital of the Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. Dr. Kanas was an associate professor, Oral and Maxillofacial Pathology, College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah, when this article was written. He now is a staff dentist, Michigan Community Dental Clinics, Port Huron. Address correspondence to Dr. Kanas at [email protected]. Disclosure. None of the authors reported any disclosures. This work was supported in part by grant H97HA075 from the Health Resource Services Administration, U.S. Department of Health and Human Services, Rockville, Md. Information on the case described in this article was presented in part as a case report at the Western Society of Teachers of Oral Pathology meeting in Kona, Hawaii, Oct. 28-30, 2012. Diagnostic Challenge is published in collaboration with the American Academy of Oral and Maxillofacial Pathology and the American Academy of Oral Medicine. 1. Mesri EA. Inflammatory reactivation and angiogenicity of Kaposi’s sarcoma-associated herpesvirus/HHV8: a missing link in the pathogenesis of acquired immunodeficiency syndrome-associated Kaposi’s sarcoma. Blood 1999;93(12):4031-4033. 2. Epstein JB, Cabay RJ, Glick M. Oral malignancies in HIV disease: changes in disease presentation, increasing understanding of molecular pathogenesis, and current management. Oral Surg Oral Med Oral Pathol
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Oral Radiol Endod 2005;100(5):571-578. 3. Semeere AS, Busakhala N, Martin JN. Impact of antiretroviral therapy on the incidence of Kaposi’s sarcoma in resource-rich and resourcelimited settings. Curr Opin Oncol 2012;24(5):522-530. 4. Katz J, Guelmann M, Stavropolous F, Heft M. Gingival and other oral manifestations in measles virus infection. J Clin Periodontol 2003;30(7):665-668. 5. Kadesh JB, Albers DD. Infectious mononucleosis first manifest by mandibular pericoronitis: report of case. Gen Dent 1981;29(5):428-429. 6. Benoliel R, Katz J. Infectious mononucleosis first manifest by pericoronitis: two case reports. Ann Dent 1989;48(1):30-32. 7. Aronovich S, Connolly TW. Pericoronitis as an initial manifestation of acute lymphoblastic leukemia: a case report. J Oral Maxillofac Surg 2008;66(4):804-808. 8. Dhanrajani PJ, Swaify GA, Khateery SM. Malignant lymphoma presenting as pericoronitis: a case report. Int J Oral Maxillofac Surg 1992;21(5):295-296. 9. Sleeman DJ, Thomas S, Telfer M, Irvine GH. Intra-oral carcinoma simulating benign oral disease. Br Dent J 1992;173(9):312-313. 10. Tornesello ML, Biryahwaho B, Downing R, et al. Human herpesvirus type 8 variants circulating in Europe, Africa and North America in classic, endemic and epidemic Kaposi’s sarcoma lesions during pre-AIDS and AIDS era. Virology 2010;398(2):280-289. 11. Hosseini-Moghaddam SM, Soleimanirahbar A, Mazzulli T, Rotstein C, Husain S. Post renal transplantation Kaposi’s sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy. Transpl Infect Dis 2012;14(4):338-345. 12. Dictor M, Rambech E, Way D, Witte M, Bendsoe N. Human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus) DNA in Kaposi’s sarcoma lesions, AIDS Kaposi’s sarcoma cell lines, endothelial Kaposi’s sarcoma simulators, and the skin of immunosuppressed patients. Am J Pathol 1996;148(6):2009-2016. 13. Ramirez-Amador V, Martinez-Mata G, Gonzalez-Ramirez I, AnayaSaavedra G, de Almeida OP. Clinical, histological and immunohistochemical findings in oral Kaposi’s sarcoma in a series of Mexican AIDS patients: comparative study. J Oral Pathol Med 2009;38(4):328-333. 14. Rosado FG, Itani DM, Coffin CM, Cates JM. Utility of immunohistochemical staining with FLI1, D2-40, CD31, and CD34 in the diagnosis of acquired immunodeficiency syndrome-related and non-acquired immunodeficiency syndrome-related Kaposi sarcoma. Arch Pathol Lab Med 2012;136(3):301-304. 15. Radu O, Pantanowitz L. Kaposi sarcoma. Arch Pathol Lab Med 2013;137(2):289-294. 16. Fatahzadeh M, Schwartz RA. Oral Kaposi’s sarcoma: a review and update. Int J Dermatol 2013;52(6):666-672. 17. Baccaglini L, Atkinson JC, Patton LL, Glick M, Ficarra G, Peterson DE. Management of oral lesions in HIV-positive patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(suppl):S50.e1-S50.e23. 18. McNutt M, Partrick M, Shugars DA, Phillips C, White RP Jr. Impact of symptomatic pericoronitis on health-related quality of life. J Oral Maxillofac Surg 2008;66(12):2482-2487. doi:10.1016/j.joms.2008.07.005. 19. Umadevi M, Adeyemi O, Patel M, Reichart PA, Robinson PG. (B2) Periodontal diseases and other bacterial infections. Adv Dent Res 2006;19(1):139-145. 20. Lopez de Blanc S, Sambuelli R, Femopase F, et al. Bacillary angiomatosis affecting the oral cavity: report of two cases and review. J Oral Pathol Med 2000;29(2):91-96. 21. Samaranayake P. Re-emergence of tuberculosis and its variants: implications for dentistry. Int Dent J 2002;52(5):330-336. 22. Piluso S, Ficarra G, Lucatorto FM, et al. Cause of oral ulcers in HIVinfected patients: a study of 19 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82(2):166-172. 23. Chinn H, Chernoff DN, Migliorati CA, Silverman S Jr, Green TL. Oral histoplasmosis in HIV-infected patients: report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79(6):710-714. 24. Arduino PG, Porter SR. Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management. Oral Dis 2006;12(3): 254-270. 25. Feller L, Wood NH, Raubenheimer EJ, Meyerov R, Lemmer J. Alveolar bone necrosis and spontaneous tooth exfoliation in an HIVseropositive subject with herpes zoster. SADJ 2008;63(2):106-110. 26. Kanas RJ, Jensen JL, Abrams AM, Wuerker RB. Oral mucosal cytomegalovirus as a manifestation of the acquired immune deficiency
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syndrome. Oral Surg Oral Med Oral Pathol 1987;64(2):183-189. 27. Delgado WA, Almeida OP, Vargas PA, Leon JE. Oral ulcers in HIV-positive Peruvian patients: an immunohistochemical and in situ hybridization study. J Oral Pathol Med 2009;38(1):120-125. 28. Anil S, Beena VT, Nair RG. Squamous cell carcinoma of the gingiva in an HIV-positive patient: a case report. Dent Update 1996;23(10): 424-425. 29. Nador RG, Chadburn A, Gundappa G, Cesarman E, Said JW,
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