hiv oral manifestation

Oral Manifestations of HIV

Presentation byDr.A.Kameswara Rao

P.G.StudentDept. of Oral pathology & Microbiology

GITAM Dental College & Hospital

Introduction

DemographicsClassification of Oral Manifestations

Individual diseases

Conclusion

Contents :

Introduction

• Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by the HIV, and is characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasm and neurologic manifestations.

• Oral manifestations of HIV infection are important in the AIDS epidemic and some of them could be used to assess the status of immunosuppression and determine the prognosis of the disease.

• Early diagnosis and appropriate treatment of oral lesions have great influence on patient’s general health and can reduce the mortality rate of the disease.

Courtesy : Ashish S. Bodhade. Oral manifestations of HIV infection and their correlation with CD4 count. Journal of Oral Science2011;53(2):203-211,

IntroductionOral lesions may:(1) Indicate HIV infection in previously undiagnosed cases(2) Predict HIV disease progression(3) Represent early clinical features of clinical AIDS (for example, oral Kaposi’s sarcoma)(4) Form traditional entry or exit determinants for antiretroviral therapy(5) Be determinants of anti-opportunistic infection therapy(6) Be used in disease staging and classification(7) Act as markers of other more subtle mucosal immunodeficiency states often missed on clinical examination(8) Lead patients to seek treatment because of pain/discomfort or aesthetic reasons(9) Individually correlate with CD4 levels in severely immunosuppressed patients(10) Correlate with CD4 levels when grouped together (11) Act as cofactors affecting the rate of HIV disease progression.

Courtesy : Iain L C Chapple, John Hamburger. The significance of oral health in HIV disease. Sex Transm Inf 2000;76:236–243.

Demographics

Since the beginning of the epidemic, almost 78 million people have been infected with the HIV virus and about 39 million people have died of HIV.

Globally, 35.0 million [33.2–37.2 million] people were living with HIV at the end of 2013.

An estimated 0.8% of adults aged 15–49 years worldwide are living with HIV, although the burden of the epidemic continues to vary considerably between countries and regions.

The National AIDS Control Organization (NACO) estimated that 1.8-2.9 million HIV-positive individuals were living with HIV/ AIDS in India in 2007.

Courtesy : WHO Global Health Observatory Data, NACO HIV Data

Classification

There are two main classification systems of oral lesions associated with HIV infection.

Based on the etiology of the oral lesions.

According to this system, orofacial lesions are classified as bacterial, viral, or fungal infections or as neoplastic lesions or other conditions.

Courtesy : Nicoleta Vaseliu. Oral Manifestations of HIV Infection .

Oral Manifestations of Acquired Immunodeficiency Syndrome (AIDS)

Infections : More Common Less Common

Fungal • Candidiasis• HIV-related gingivitis

• Aspergillosis• Histoplasmosis• Cryptococcosis• Geotrichosis

Bacterial • HIV-associated periodontitis• NUG

• Mycobacteriumavium• Klebsiella pneumoniae• Enterobacter • Escherichia coli• Salmonella enteritidis• Cat-scratch disease• Sinusitis• Exacerbation of periapical

inflammatory disease• Submandibular cellulitis

Viral • HSV• VZV• EBV

• HPV• CMV

Courtesy : Neville. Oral and Maxillofacial pathology.2nd edition.pp237-240

Oral Manifestations of Acquired Immunodeficiency Syndrome (AIDS) More Common Less Common

Neoplasms : Kaposis sarcoma Non-Hodgkin's lymphomaSquamous cell carcinoma

Lymphadenopathy Cervical

Neurologic Trigeminal neuropathyFacial palsy

Miscellaneous Aphthous ulcerationsNecrotizing stomatitisToxic epidermolysisDelayed wound healingThrombocytopeniaXerostomia or sicca like syndromeHyperpigmentationGranuloma annulareExfoliative cheilitislichenoid reactions


Classification

The second, more widely used, system—recommended by the EC Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Human Immunodeficiency Virus—classifies orofacial lesions into three groups according to the degree of their association with HIV infection.

Courtesy : Classification and diagnostic criteria for oral lesions in HIV infection. JOPM 1993;22(7): 289-291.


Group 1Lesions strongly associated with HIV infection

Candidiasis – Erythematous – PseudomembranousHairy leukoplakia Kaposi’s sarcoma Non-Hodgkin’s lymphoma Periodontal disease – Linear gingival erythema – Necrotizing (ulcerative) periodontitis – Necrotizing (ulcerative) gingivitis


Group 2Lesions less commonly associated with HIV infection

Bacterial infections – Mycobacterium avium-intracellulare – Mycobacterium tuberculosis • Viral infections Herpes Simplex virusHuman papillomavirus (wart-like lesions) – Condyloma acuminatum – Focal epithelial hyperplasia Verruca vulgaris Varicella zoster virus Herpes zoster Varicella

• Melanotic hyperpigmentation • Necrotizing (ulcerative) stomatitis• Salivary gland disease – Dry mouth due to decreased salivary flow rate – Unilateral or bilateral swelling of the major salivary glands • Thrombocytopenic purpura • Ulceration NOS (not otherwise specified)


Group 3Lesions seen in HIV infection

Bacterial infections Actinomyces Israel Escherichia coli Klebsiella pneumoniae Cat-scratch disease • Viral infections Cytomegalovirus Molluscum contagiosum Fungal infection other than candidiasis Cryptococcus neoformans Geotrichum candidum Histoplasma capsulatum mucormycosis/ zygomycosis Aspergillus flavus

• Drug reactions (ulcerative, erythema multiforme, lichenoid, toxic epidermolysis.) • Epithelioid (bacillary) angiomatosis • Neurologic disturbances Facial palsy Trigeminal neuralgia

Classification

Reduction of circulating CD4 count is the main criteria for assessing the immunosuppression status in HIV-positive patients.

The normal number of circulating CD4 cells ranges from 600 to 1600 cells/mm³, but the initial signs of immunosuppression occur when CD4 count is lower than 500 cells/mm3.

Courtesy : Mithra N. Hegde et al. Oral lesions and immunosuppression in HIV patients. Biodiscovery 2012 ;(4)3:1-6.

WHO immunological classification on the basis of CD4 count

Group 1 >500/ml

Group2 Mild 350-499/ml

Group 3 Advanced 200-349/ml

Group 4 Severe <200/ml

Courtesy : Mithra N. Hegde et al. Oral lesions and immunosuppression in HIV patients. Biodiscovery 2012 ;(4)3:1-6.

Classification

Candidiasis

The most common intra oral manifestation of HIV infection.

Based on clinical appearance, oral candidiasis can appear as erythematous or atrophic candidiasis, pseudomembranous candidiasis, hyperplastic or chronic candidiasis, and angular cheilitis.

Courtesy : Jha R et al:. Oral Manifestations of HIV-AIDS: A Diagnostic and Management Dilemma. Journal of Research in Medical and Dental Science 2014:2(1):96-102 |

Pseudomembranous CandidiasisThe pseudomembranous form of candidiasis is characterized by the presence of multifocal smooth white papular lesions that can usually be rubbed away, leaving a red surface, and surface pseudohyphae can be readily detected.

Courtesy : Louis de Repentigny et al. Immunopathogenesis of Oropharyngeal Candidiasis in Human Immunodeficiency Virus Infection. CLINICAL MICROBIOLOGY REVIEWS 2004,:17(4)729–759

Pseudomembranous CandidiasisHyphae are numerous and extend into the spinous cell layer in pseudomembranous candidiasis, accompanied by parakeratosis, acanthosis, and spongiosis of the infected superficial epithelium . An abundant mononuclear cell response is observed in the submucosa


Erythematous CandidiasisThe erythematous form presents as diffuse and multiple foci of macular erythema involving the palate, oropharynx, buccal mucosa, and dorsal tongue, but hyphae are frequently absent, while blastoconidia may be found on an atrophic epithelial surface.


Erythematous CandidiasisCharacterized by abundant neutrophilic micro abcesses in the parakeratin layer of the epithelium, while microabcesses are rarely found in pseudomembranous candidiasis. An abundant mononuclear cell response is observed in the submucosa


Chronic Hyperplastic Candidiasis- severe immune suppression /long standing disease. white non removable plaque which may be stained by food. can occur on any mucosal surface.


Angular ChelitisRadiating fissures from labial commissure, sometimes covered with a pseudomembrane.

Hyper keratosis may be seen peripheral to the fissures.

opening of mouth becomes restricted and painful.


Candidal speciesThe majority of patients are infected with C. albicans,

Other species are Candida tropicalis, Candida parapsilosis,Candida guillermondii, Candida glabrata, (Sole cause of recurrent candidiasis)Candida dubliniensis.

Depletion of CD4+ cells below a critical threshold of 200 cells/mm3 most often triggers the onset of candidiasis


PathogeneisThe ability of C. albicans to infect such diverse host niches is supported by a wide range of virulence factors and fitness attributes.

A number of attributes, including the morphological transition between yeast and hyphal forms, the expression of adhesins and invasins on the cell surface, thigmotropism, the formation of biofilms, phenotypic switching and the secretion of hydrolytic enzymes are considered virulence factors.

Rapid adaptation to fluctuations in environmental pH, metabolic flexibility, powerful nutrient acquisition systems are other attributes.

Courtesy : François L. Mayer. Candida albicans pathogenicity mechanisms. Virulence 2013:4(2)119–128.

PolymorphismsC. albicans is a polymorphic fungus that can grow either

as ovoid-shaped budding yeast, as elongated ellipsoid cells with constrictions at the septa (pseudohyphae) or as parallel-walled true hyphae.

Further morphologies include white and opaque cells, formed during switching, and chlamydospores, which are thick-walled spore-like structures


TransitionThe transition between yeast and hyphal growth forms is termed dimorphism.

The hyphal form is more invasive than the yeast form.

Smaller yeast form is believed to represent the form primarily involved in dissemination


Factors influencing transition

Yeast Hyphae

Low pH (<6) high pH (> 7)

starvation,the presence of serum or N-acetylglucosamine, physiological temperature and CO2

In healthy individuals

Salivary flow protects the oral cavity by dislodging yeasts and bacteria, which are then removed by swallowing and this process may be facilitated by binding of C. albicans to salivary mucins or to a nonmucin proteoglycan.


In HIV PatientsIn patients with advanced HIV infection, the salivary flow rate is reduced by 40%.

The incidence of oral candidiasis is also enhanced in patients with acidic saliva , and a low pH increases the adherence of C. albicans to epithelial surfaces.

Glucose supplementation of saliva augments the growth rate and the resulting acidic pH provides the required environment for activity of Candida secretory aspartyl proteinases, (Saps) which enhance virulence by degrading mucins, which play an important role in lubrication of epithelial surfaces and host defense.


Adhesions C. albicans has a specialized set of proteins (adhesins) which mediate adherence to other C. albicans cells to other microorganisms, to abiotic surfaces and to host cells.

Agglutinin-like sequence (ALS) proteinsHypha-associated glycosyl phosphatidyl inositol-linked proteincell-surface associated proteasesintegrin-like surface protein


Invasion


Induced endocytosis Active penetration

Expresses specialized proteins on the cell surface (invasins) that mediate binding to host ligands (such as E-cadherin on epithelial cells and N-cadherin on endothelial cells, thereby triggering engulfment of the fungal cell into the host cell.

Secreted aspartic proteasesLipasesPhospholipases, (detaches epithelial cell desmosomes)

Even non viable fungi can enter the cell Only viable fungi can enter

Non Immunological DefenseSeveral salivary anticandidal proteins, including lysozyme, lactoferrin, the histatins, calprotectin, and antileukoprotease, inhibit the growth of C. albicans and its attachment to the oral epithelium.


In healthy individuals In HIV

Lysozyme Hydrolysis of N-glycosidic linkages in the microbial cell wall and injury to the cytoplasmic membrane

Levels are increased and so the activity of lysozyme is doubtful

Lactoferrin damage to the fungal cell wall and activation of intracellular autolytic enzymes

Levels may be normal, decreased or increased because of source is from submandibular gland not parotid


In healthy individuals In HIV

Histatins disrupt cell membranes decreased concentrations of histatins causes increased tendency to oral candidiasis

Calprotectin inhibits the growth by depriving the fungus of zinc

concentrations of calprotectin are deficient in HIV-infected patients

Antileukoprotease Unknown Decreased

Non Immunological Defense

Biofilm FormationCatheters, dentures (abiotic) and mucosal cell surfaces (biotic) are the most common substrates.

Biofilms form in a sequential process including adherence of yeast cells to the substrate, proliferation of these yeast cells, formation of hyphal cells in the upper part of the biofilm, accumulation of extracellular matrix material and, finally, dispersion of yeast cells from the biofilm complex


HydrolasesFollowing adhesion to host cell surfaces and hyphal growth, hyphae secrete hydrolases to facilitate active penetration into the cells.

They are : proteases, phospholipases and lipases.


Immunological Defenceglucan and chitin, mannan contents of cell wall are recognised by the Toll Like Receptors.

TLR-2 and TLR-4 represent the main TLRs involved in the signalling cascades


TreatmentTreatment is much more difficult in patients with AIDS.

Nystatin often is ineffective.

Topical clotrimazole is associated with an improved response.In spite of this success, topical therapy is associated with a high recurrence rate .

The systemic azoles (fluconazole, ketoconazole, itraconazole) produce longer disease-free intervals but itraconazole and ketoconazole require gastric acidity for adequate absorption, and all three agents are associated with a number of drug interactions.

In addition, widespread use of systemic azoles has led to an increased prevalence of drug- resistant candidiasis.


Oral Hairy LeukoplakiaOral hairy leukoplakia (OHL) was first discovered by Greenspan in 1984 and was described as asymptomatic, white, nonscrapable, vertically corrugated hyperkeratotic hair-like projections that appear on the lateral border of the tongue.

Caused by the Epstein–Barr Virus (EBV), the lesion is said to be an early indicator of an immune deficiency status rather than being a marker for HIV infection.

Courtesy : Ajay Reginald and B. Sivapathasundharam.. Oral hairy leukoplakia: An exfoliative cytology study. Contemp Clin Dent. 2010 Jan-Mar; 1(1): 10–13. .

CytologyCowdry A inclusion bodies: an eosinophilic and central intranuclear inclusion body surrounded by a clear space

Courtesy : Ajay Reginald and B. Sivapathasundharam.. Oral hairy leukoplakia: An exfoliative cytology study. Contemp Clin Dent. 2010 Jan-Mar; 1(1): 10–13. .

Ground glass nuclei: an eosinophilic or basophilic inclusion body homogenizing the whole surface and exhibiting peripheral margination of chromatin

HistopathologyOHL is characterized by acanthosis of the surface epithelium and irregular hyperkeratosis.

Ballooning of epithelial cells is noted within the superficial stratum spinosum.

Peripheral beading of the chromatin in superficial epithelial cells is characteristic of the lesion results from the multiplication of EBV

Courtesy : Joanne Leger Prasad. Oral hairy leukoplakia in patients without HIV: presentation of 2 new cases. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2014,;118,(5): e151–e160

http://www.sciencedirect.com/science/journal/22124403/118/5

TreatmentTreatment of OHL usually is not needed, although slight discomfort or aesthetic concerns may necessitate therapy.

Acyclovir produces rapid resolution but recurrence is expected with a discontinuationof therapy.

Topical treatment with retinoids or podophyllum resin has resulted in temporary remissions.

In addition, HIV therapy with zidovudine appears to affect EBV and result in significant regression .


Kaposis Sarcoma(KS)First described by the Hungarian dermatologist Moritz Kaposi in 1872, KS is a multifocal neoplasm of vascular endothelial cell origin.

KS is traditionally separated into four different types: Classic: which primarily affects elderly men of Mediterranean and

eastern European origin; Endemic: which is common in parts of Africa; (lymphadenopathic)Epidemic or AIDS-associated; and Transplantation-associated.

Courtesy : Kishore Shetty. Management of oral Kaposi’s sarcoma lesions on HIV-positive patient using highly active antiretroviral therapy: Case report and a review of the literature. Oral Oncology Extra October 2005 ;41(9) :226–229.

Courtesy : Gnepp. Diagnostic Surgical pathology of Head and Neck 2nd edition;238-239.

Classic` Endemic Transplantation HIV Associated

affects older malesof Italian, Slavic, or Jewish ancestry

endemic toyoung African children

seen in 1% to 4% of renal transplant recipients

often as an early sign ofthe disease. young adultsAverage Age :39 yrs

often associated with altered immune states as wellas lymphoreticular and other malignancies

presents as a localized or generalizedenlargement of lymph node chains, including the cervical nodes.

Cutaneous multifocal blue-red nodules develop on the lower extremities and slowly increase in size and numbers,

follows a fulminating course with visceral involvement and minimal skin or mucous membraneinvolvement.

Sarcomatous involvementoccurs on the skin as well as in internal organs

cutaneous locations, especially alonglines of cleavage and on the tip of the nose.

Oral involvement inthis form of the disease is quite unusual,

Salivary glands are effected

oral mucosal lesions are rare

strong predilectionfor palatal, gingival, and lingual mucosa

Clinical featuresEarly oral mucosal Kaposi sarcoma is flat and slightly blue, red, or purple that do not blanch on pressure.

With time, the lesion becomes more deeply discolored, and surface papules and soft nodules develop, usually remaining less than 2 cm in size.


Clinical features

If the lesion overlies bone, it may invade and/ or necrose the bone, and occasional lesions are so hemorrhagic or so painful.

Individual lesions may coalesce, and occasional patients never develop the nodular variant.

Cervical lymph node and salivary gland enlargement may also be seen.


EtiologyIn 1994 HHV-8/KSHV was first detected in KS specimens.

KSHV is now considered the causative agent of AIDS-associated, classic, endemic, andiatrogenic KS.

Courtesy : Badari Rao. Kaposi’s sarcoma: Insights into its understanding. International Journal of Contemporary Dental and Medical Reviews (2014), Article ID 031114, 4 Pages

PathogenesisThe pathogenesis of AIDS-associated KS is multifactorial and involves KSHV, altered expression and response to cytokines and stimulation of KS growth by HIV trans-activation protein (tat).

KSHV is a necessary but solely not a sufficient cause of KS.

It encodes protein homologs of interleukin-6, chemokines of the macrophage inflammatory protein family, cell cycle regulators of the cyclin family, and anti-apoptotic genes of the bcl-2 family.

The HIV tat protein can promote the growth of spindle cells of endothelial origin but only in the presence of inflammatory cytokines


Pathogenesis


circulating KS progenitor cells and cells latently infected with KSHV seek sites of pre-existing inflammation like periodontal disease sites

Exposure to inflammatory cytokines - IFN-α results in differentiation of latently infected cells into KS-like spindle cells and induces KSHV reactivation

reactivation of KSHV leads to expression of pathogenic genes such as viral IL-6 that in turn activate vascular endothelial growth factor and induce angiogenesis;

the creation of inflammatory angiogenic environment increases the availability of infectable cells, i.e. endothelial and KS spindle cells

cells become responsive to HIV tat protein which augments the inflammatory angiogenic state by the increasing basic fibroblast growth factor, IFN-α, and VEGF

Histological featuresHas a similar histopathologic appearance in all its clinical subtypes.

The early lesion (patch stage) is characterized by a proliferation of small veins and capillaries around one or more dilated vessels.

A pronounced mononuclear inflammatory cell infiltrate, including mast cells, is often noted, as are scattered erythrocytes and hemosiderin deposits.

There may be an inconspicuous perivascular proliferation of spindle cells, but cellular atypia is minimal.


Histological featuresMore advanced lesions are nodular and show increasednumbers of small capillaries or dilated vascular channels interspersed with proliferating sheets of sarcomatous or atypical spindle cells, often with large numbers of extravasated erythrocytes and abundant hemosiderin deposition.

Slit like vascular channels without a visible endothelial lining are typically interspersed within the spindle cells.

Lesion cells have somewhat enlarged, hyperchromatic nuclei with mild to moderate pleomorphism


TreatmentKS responds to radiation or systemic chemotherapy (singly or in combination), such as vinblastine, vincristine. etoposide, bleomycin, Adriamycin, actinomycin D, doxorubicin, or alpha-interferon.

Oral lesions frequently are a cause of major morbidity, as a result of pain, bleeding, and functional interferences.

Intralesional injection of oral lesions with vinblastine is effective and may be repeated if required .

Intralesional injection of a sclerosing agent, sodium tetradeeyl sulfate, has been effective for problematic intraoral lesions less than 2.5 cm in diameter.

Problematic lesions also may be removed by surgical excision, cryotherapy, laser ablation. Courtesy : Gnepp. Diagnostic Surgical pathology of Head and Neck 2nd edition;238-239.

Non Hodgkin’s LymphomaHigh-grade NHL was first reported in 1984.

The relative risk of NHL among HIV-infected patients is 150-250-fold higher than in the general population.

Incidence of NHL accounts for 2%–3% of newly diagnosed AIDS cases and occurs when CD4+ count is less than 100cells/ml.

HIV-associated lymphomas include (1) high-grade B-cell lymphomas: Burkitt lymphoma, diffuse large B-cell lymphoma with centroblastic features and with immunoblastic features and (2) unusual lymphomas, “primary effusion lymphoma” and “plasmablastic lymphoma” of the oral cavity.

Courtesy : Dattatray G. Saple et al. Lymphoma in HIV patients: Varied presentations. Indian J Med Paediatr Oncol. 2010;31(1)39–42.

Courtesy : Prakash Vishnu and David M. Aboulafia.. AIDS-Related Non-Hodgkin's Lymphoma in the Era of Highly Active Antiretroviral Therapy. Advances in Hematology

Volume 2012, Article ID 485943, 9 pages

WHO Classification of lymphoid malignancies associated with HIV infection

Lymphomas also occurring in immunocompetent patientsBurkitt and Burkitt-like lymphomasDiffuse large B-cell lymphomas Centroblastic Immunoblastic (including primary CNS lymphoma)Extranodal MALT lymphoma Peripheral T-cell lymphoma Classical Hodgkin lymphoma

Lymphoma occurring more specifically in HIV-positive patientsPrimary effusion lymphomaPlasmablastic lymphoma of the oral cavity

Lymphoma occurring in other immunodeficiency statesPolymorphic B-cell lymphoma (PTLD-like)

Pathogenesis

Courtesy : Tom Powles, Gail Matthews, Mark Bower. AIDS related systemic non-Hodgkin’s lymphoma. Sex Transm Inf 2000;76:335–341.

Defective T Cell Surveillance long term stimulation and proliferation of B lymphocytes

immune stimulation by HIV and reactivation of previous EBV infection

In the absence of EBV infection HIV induces the production of inflammatory cytokines that cause B cell stimulation, proliferation, and activation

cell lines derived from AIDS related NHL have been found to express cytokines including interleukin 6, interleukin 10, and tumour necrosis factor α

Burkitt Lymphoma

Burkitt’s Lymphoma (BL) is a highly aggressive form of Non–Hodgkin’s lymphoma which was first described in 1958 by Dennis Burkitt in Africa.

EBV infection and chromosomal translocation resulted in dysregulation of c-MYC oncogene are the etiological factors.

Courtesy : Soujanya Pinisetti. HIV Associated Intra–oral Burkitt’s Lymphoma: A Case Report. J Clin Diagn Res. 2013 Dec; 7(12): 3088–3089.

Endemic Sporadic Immunodeficiency Associated

Endemic to young African children

occurs worldwide, with no specific geographic or climatic association.

often as an early sign ofthe disease. young adultsAverage Age :39 yrs

Involves jaw bones, kidneys, GIT, ovaries and breast

involves abdomen and ileocecal areas.accounts for 1–2% of lymphomas in adults and for 40% of lymphomas in children

accounts for 30-40% of Non-Hodgkin’s lymphomas


Classification

Clinical features: HIV patients with Burkitt’s lymphoma are usually younger as compared to patients with diffuse large B cell lymphomas and they have CD4 counts greater than 200 cells/μl.

Manifests as a soft tissue mass with or without ulceration, tissue necrosis and it occurs commonly on gingiva, palate and alveolar mucosa, with rapid growth and destruction .

The earliest clinical sign of Burkitt’s lymphoma of jaws is mobility and exfoliation of the teeth


PathogenesisHIV infection causes polyclonal activation of B cells in an uncontrolled manner.

The genetic instability of EBV positive, aberrantly regulated B cells leads to a risk of c-myc rearrangement and then, to lymphoma.

C-myc rearrangement is a crucial event in lymphoma genesis


HistologyClassic Plasmacytoid Atypical

characterized by a mass of diffuse, neoplastic, non–cleaved uniform, medium sized B- lymphocytes with round nuclei and multiple nucleoli of with numerous mitotic figures admixed with numerous tangible body macrophages with apoptotic debris, giving a picture of “starry sky”.

Shows a typical “starry sky” appearance with an infiltrate of neoplastic lymphoid cells . Under higher magnification, these medium-sized neoplastic lymphoid cells were characterized by abundant basophilic cytoplasm and an eccentric nucleus, suggestive of plasmacytoid differentiation

Diffuse infiltrate of atypical lymphoid cells with abundant apoptotic debris and scattered tingible body macrophages.

accounts for 1–2% of lymphomas in adults and for 40% of lymphomas in children

oral mucosal lesions are rare

Large B Cell LymphomaDiffuse large B-cell lymphoma (DLBCL) is the most common of the aggressive NHLs in the United States.

80% of the cases are composed of cells resembling germinal center centroblasts.

The immunoblastic type (10% of the cases) has more than 90% immunoblasts.

Other morphologic variants include the T-Cell–Rich/Histiocyte-Rich variant which has a prominent background of reactive T cells and histiocytes.

Courtesy : Jonathan W. Friedberg . Diffuse Large B-Cell Lymphoma. Hematol Oncol Clin North Am. 2008 Oct; 22(5): 941–ix.

Linear Gingival ErythemaThis unusual pattern of gingivitis appears with a distinctive linear band of erythema that involves the free gingival margin and extends 2 to 3 mm apically .

The alveolar mucosa and gingiva may demonstrate punctate or diffuse erythema.

This form of gingivitis does not respond to improved plaque control and often exhibits a greater degree of erythema than would be expected for the amount of plaque in the area.


Linear Gingival Erythema

It is of questionable etiology and pathogenesis while not all the cases show distinct fiery red band along the gingival margin.

However c.albicans can be isolated in more than 50% of cases.

Courtesy : elegraki, Arista. Paediatric AIDS--related linear gingival erythema: a form of erythematous candidiasis? J Oral Pathol M.ed 1999 Apr;28(4):178-82.

Necrotising ulcerative gingivitis

Refers to ulceration and necrosis of one or more inter dental papillae with no loss of periodontal attachment.

Patients with NUG have interproximal gingival necrosis, bleeding, pain , and halitosis.


Necrotising ulcerative gingivitis

NUG the immunosuppression may be induced by stress or poor diet.

Smoking in subjects with poor oral hygiene also contributesto both.

ANUG is a fusospirochaetal infection involving Treponema vincentii and Fusobacterium nucleatum.

Courtesy : Iain L C Chapple, John Hamburger. The significance of oral health in HIV disease. Sex Transm Inf 2000;76:236–243.

Necrotising ulcerative peridontitisCharacterized by gingival ulceration and necrosis associated with rapidly progressing loss of periodontal attachment.

Although severe cases can affect all teeth, multiple isolated defects often are seen and contrast with the diffuse pattern associated with typical chronic periodontitis.

Edema, severe pain, and spontaneous hemorrhageare common.

Deep pocketing usually is not seen because extensive gingival necrosis typically coincides with loss of the adjacent alveolar boneCourtesy : Neville. Oral and Maxillofacial pathology.2nd edition.pp237-240

Necrotising Stomatitis

In patients with gingival necrosis, the process occasionally extends away from the alveolar ridges , more than 10 mm beyond the gingival margin and creates massive areas of tissue destruction termed necrotizing stomatitis.

The process clinically resembles noma and may involve predominantly soft tissue or extend into the under lying bone, resulting in extensive sequestration.


TreatmentThe treatment of NUG and NUP revolves around debridement, anti microbial therapy, immediate follow up care, and long-term maintenance.

The initial removal of necrotic tissue is necessary combined with povidine iodine irrigation.

The use of systemic antibiotics usually is not necessary, but metronidazole has been administered to patients with extensive involvement that is associated with severe acute pain.

All patients should use chlorhexidine mouth rinses initially and for long- term maintenance.

Monthly recalls are necessary until the process stabilizes; evaluations then are performedevery 3 months.Courtesy : Neville. Oral and Maxillofacial pathology.2nd edition.pp237-240

Aphthous Ulcers

Lesions that are similar clinically to aphthous ulcerations occur with increased frequency in patients infected with HIV.

All three forms (minor, major, and herpetiform) are seen.

As immunosuppression becomes more profound, major aphthous ulcerations demonstrate an increased prevalence.


HPV InfectionHPV is responsible for several facial and oral lesions in immunocompetent patients.

Most frequent of which are the verruca vulgaris(common wart) and oral squamous papilloma.

An increased prevalence of HPV-related lesions is noted in HIV- infected patients, and most are located in the anogenital areas.

HIV-infected patients often demonstrate more unusual variants such as HPV- 7 (associated with butcher 's warts) or HPV-32 (often noted in Heck's disease)


Courtesy :Barnes. Surgical pathology of head and neck.211-215.

Papilloma Focal epithelial hyperplasia

Most common of benign epithelial tumors of the oral cavity Benign hyperplastic lesion of the oral cavity that is caused by HPV infection

Exophytic proliferations arranged in a finger-like configuration, giving a cauliflower-like clinical appearance. Majority are pedunculated, some are sessile.

circumscribed, sessile, soft, and elevated nodules of the oral mucosa . Although beginning as separate nodules, the lesions often become confluent and cover large areas of the oral mucosa of the lips and buccal surfaces as well as the tongue

Squamous papillomas are small exophytic lesions with a central fibrovascular core covered by stratified, parakeratinizedepithelium

Acanthosis and elongation and anastomosing of the rete ridges, do not form fibrovascular cores as seen in papillomas.

Courtesy :Barnes. Surgical pathology of head and neck.211-215.

Verruca vulgaris Condyloma acuminatum

warty exophytic lesion that resembles verrucae in other sites, including the skin. It is caused by the HPV

oral wart, moist wart, caused by HPV and appears one to three months after exposure

Young adults and children are most often affected. Itis thought that autoinoculation of virus.Verruca have an entirely exophytic growth pattern. Common sites include the lips, palate, alveolar ridge, and gingiva

appear as soft verrucous nodules or multiple adjacent papillary clusters that tend to coalesce into soft, pink cauliflower-like masses, although isolated lesions may occur

Reveals long vascular cores coated in thick layers of epithelialcells that form pointed projections. Rete ridges often seem to radiate outward from a central point. Koilocytes are often noted

Pronounced spinous layer hyperplasia and cellular ballooning, andmitoses are seen extending into the spinous layer. The base of the rete ridges are often bulbous. The lesions show parakeratosis, acanthosis, and papillomatosis. the base is sessile, and there is parakeratin crypt formation

Molluscum contagiosumMolluscum contagtosum is an infection of the skin caused by a poxvirus .

The lesions are small, waxy, dome-shaped papules thatoften demonstrate a central depressed crater.

In immuno competent individuals, the lesions are self- limiting and typically involve the genital region or trunk.

5% to 10% of HIV-infected patients are affected and the facial skin commonly is involved


Molluscum contagiosumSurface epithelium forms several hyperplastic downgrowths.

This involuting epithelium contains numerous large. intracytoplasmic inclusions known as molluscum bodies.

In the center of the lesion, the keratin layer often disintegrates and releases the adjacent molluscum bodies, hence the central crater.


Histological features

Small fungal organisms are visible within the cytoplasm of histiocytes and multinucleated giant cells.

These phagocytic cells may be present in sheets or in organized granulomas


Herpes SimplexEarly in the course of HIV disease, HSV infections are usually self-limited.

Grouped lesions appear, ulcerate, and heal, usually in less than 2 weeks.

Presence of mucocutaneous HSV infection for longer than 1 month is suggestive of advanced HIV infection.

Tender, often painful, ulcerative lesions of the lip are the hallmark of HSV in HIV-infected patients.

Courtesy : Jordan W. Tappero et al Cutaneous Infections In Hiv-infected Patients. Clinical Microbiology Reviews.1995;8(3):440–450.

Histological featuresThe virus exerts its main effects on the epithelial cells.

Infected epithelial cells exhibit acantholysis, nuclear clearing, and nuclear enlargement, which has been termed ballooning degeneration.

The acantholytic epithelial cells are termed Tzanck cells.

Nucleolar fragmentation occurs with a condensation of chromatin around the periphery of the nucleus.

Multinucleated, infected epithelial cells are formed when fusion occurs between adjacent cells

Courtesy : Neville. Oral and Maxillofacial pathology.2nd edition.pp 217-219.

Herpes ZosterHIV-infected persons may develop primary varicella (chicken pox) when exposed to VZV for the first time .

In addition, serum antibodies to VZV do not appear to prevent varicella in HIV-infected persons, and varicella can recur.

Varicella infections typically follow a benign course, with resolution of scattered vesicular lesions in the absence of therapy.

Onset of disease occurring with average CD4 lymphocyte counts of 315 cells per mm3.


Herpes ZosterAmong HIV-infected children, HZ may develop rapidly following primary VZV infection

HZ in asymptomatic HIV-infected patients typically pursues a benign course, with resolution of vesiculobullous lesions over2 to 3 weeks, often without specific antiviral chemotherapy.

However, severe painful ulcerations followed by postherpeticneuralgia upon healing are not uncommon.

In addition, recurrent HZ occurs in up to 22% of HIV-infectedPatients.


Herpes Zoster

In addition to the vesiculobullous lesions commonly seenwith disseminated VZV, patients with advanced HIV infectionmay develop unusual lesional patterns associated with acyclovirresistance: ecthymatous, crusted, punched out ulcerations ortrue verrucous lesions, which may be seen alone or inassociation with the vesicular, ecthymatous lesions.


Cytomegalo virusCMV-related oral ulcerations, although infrequent, are a recognized complication of HIV infection.

The diagnosis of oral CMV is based upon the presence of large intranuclear and smaller cytoplasmic CMV inclusions in the endothelial cells at the base of the ulcerations.

These infections usually manifest in stage IV of the infection when there is advanced immunosupression with a CD4 count below 50.

Courtesy : Smrati Bajpai and A. R. Pazare. Oral manifestations of HIV. Contemp Clin Dent. 2010;1(1)1–5.

Tuberculosis

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis.

Worldwide, more than 1 billion people are infected, with 8 million new cases and 3 million deaths per year.

The HIV epidemic, increased immigration from countries with endemic tuberculosis, transmission of tuberculosis in crowded or unsanitary environments, and a decline of the health care infrastructure are the main causes for transmission.

Most infections are the result of direct person-to- person spread through airbornedroplets from a patient with active disease.

Courtesy : Neville. Oral and Maxillofacial pathology.2nd edition.pp173-175.

Tuberculosis


Primary Secondary Disseminated

Occurs in previously unexposed people

active disease usually develops later in life from a reactivation of organisms in a previously infected person . This reactivation is typically associated with compromised host defenses and is called secondary tuberculosis

Diffuse dissemination through the vascular system may occur and has been termed miliary tuberculosis.

Almost always involves the lungs.The organism initially elicits a nonspecific, chronic inflammatory reaction.

Secondary tuberculosis often is associated with old age. povert y. and crowded living conditions. AIDS represents one of the strongest risk factors for progression from infection to disease.

Clinical Features

Primary tuberculosis is usually asymptomatic. Occasionally, fever and pleural effusion may occur.

Classically, the lesions of secondary tuberculosis are located in the apex of the lungs but may spread to many different sites by expectorated infected material or through the lymphatic or vascular channels.

Patients have a low-grade fever, malaise, anorexia,weight loss, and night sweats.

With pulmonary progression a productive cough develops often with hemoptysis or chest pain.


Clinical Features

Head and neck involvement is not rare.

The most common extrapulmonary sites in the head and neck are the cervical lymph nodes followed by the larynx and middle ear.

Much less common sites include the nasal cavity, nasopharynx, oral cavity, parotid gland, esophagus, and spine.


Oral manifestations

Oral lesions of tuberculosis arc uncommon, with most cases appearing as a chronic painless ulcer.

Less frequent presentations include nodular, granular, or (rarely) firm leukoplakic areas.

Most of the lesions represent secondary infection from the initial pulmonary lesions.

It is unclear whether these develop from hematogenous spread or from exposure to infected sputum.


Oral manifestations

Primary oral tuberculosis without pulmonary involvement is rare.

When present, primary oral tuberculosis usually involves the gingiva, mucobuccal fold and areas of inflammation adjacent to teeth or in extraction sites.

Secondary oral lesions are mostly present on the tongue, palate and lip.


Histological features

Granulomas, which are circumscribed collectionsof epithelioid histiocytes, lymphocytes, and multinucleatedgiant cells, often with central caseous necrosis are seen.

In a person with tuberculosis, one of these granulomas is called a tubercle, Special stains , such as the Ziehl- Neelsen or other acid-fast stains, are required to demonstrate the mycobacteria


Histoloplasmosis

Histoplasmosis. the most common endemic respirator y fungal infection produced by Histoplasma capsulatum .

In healthy patients. the infection typically is subclinical and self- limiting, but clinically evident infections do occur in immuno compromised individuals.

Although a number of deep fungal infections are possible in patients with AIDS, histoplasmosis is the most common , with disseminated disease noted in approximately 5% of AIDS patients residing in areas where the fungus is endemic


Clinical featuresThe signs and symptoms associated with dissemination are nonspecific and include fever, weight loss, splenomegaly, and pulmonary infiltrates.

Oral lesions are not uncommon and usually are caused by blood borne organisms or spread from pulmonary involvement.

The most common oral presentation of histoplasmosis is a chronic, indurated mucosal ulceration with a raised border.

The oral lesions may be singular or multiple and any area of the oral mucosa may be involved.


CryptococcosisCryptococcosis is a relatively uncommon fungal disease caused by the yeast Cryptococcus neoformans.

This organism normally causes no problem in immunocompetent people, but it can be devastating to the immunocompromised patient.

It is the most common life threatening fungal infection in HIV patients.

The disease has a worldwide distribution because of its association with the pigeon.

Grows as a yeast both in the soil and in infected tissue.

The organism usually produces a prominent mucopolysaccharide capsule.


Clinical featuresPrimary cryptococcal infection of the lungs is often asymptomatic;

However, a mild flulike illness may develop.

Patients complain of productive cough, chest pain, fever and malaise.

Dissemination of the infection is common in immuno compromised patients, and the most frequent site of involvement is the meninges, followed by skin, bone and the prostate gland.

The lesions appear as erythematous papules or pustules that may ulcerate discharging a pus like material rich in cryptococcal organisms Courtesy : Neville. Oral and Maxillofacial pathology.2nd edition.pp237-240

Mucormycosis

Zygomycosis is an opportunistic, frequently fulminant, fungal infection that is caused by class Zygomycetes, including Absidia, Mucor, Rhizomucor, and Rhizopus.

Zygomycosis may involve any one of several areas of the body, but the rhinocerebral form is most relevant to the oral health care provider.


Clinical features

Patient’s may experience nasal obstruction, bloody nasal discharge, facial pain or headache, facial swelling or cellulitis, and visual disturbances with concurrent proptosis.

Symptoms related to cranial nerve involvement (e.g., facial paralysis) are often present .

With progression of disease into the cranial vault, blindness, lethargy, and seizures maydevelop, followed by death .


Oral manifestationsIf the maxillary sinus is involved, the initial presentation may be seen as intraoral swelling of the maxillary alveolar process, the palate, or both.

If the condition remains untreated, palatal ulceration may evolve, with the surface of the ulcer typically appearing black and necrotic.

Massive tissue destruction may result if the condition is not treated.


Histological featuresShows extensive necrosis with numerous large, branching, non septate hyphae at the periphery.

The hyphae tend to branch at 90-degree angles.

The extensive tissue destruction and necrosis is due to the preference of the fungi for invasion into small blood vessels.

This disrupts normal blood flow to the tissue, resulting in infarction and necrosis.


Salivary gland diseaseHIV-associated salivary gland disease also can arise anytime during infection.

Clinically obvious salivary gland disease is noted in approximately 5% of HIV- infected patients, with a greater prevalence noted in children.

The main clinical sign is salivary gland enlargement, particularly affecting the parotid.

Bilateral involvement is seen in about 60% of the patients with glandular changes and often is associated with cervical lymphadenopathy.


Diffuse Infiltrative lymphoctosis SyndromeDILS is a disorder in patients with HIV-1, characterized by salivary and lacrimal glandular swelling and sicca symptoms of varying intensity, frequently accompanied by persistent circulating and visceral CD8-positive lymphocytic infiltration.

The reported prevalence varies between 0.85 – 3%.

Patients with DILS generally present in an early HIV stage, havehigher CD4+ cell counts (commonly above 200/μl).

Most of the patients have CD8+ lymphocytosis (counts > 835/μl) and some CD8+ hyper lymphocytosis (counts > 1500/μl).

Courtesy : Levay. Diffuse Infiltrative Lymphocytosis Syndrome. SA Fam Pract 2008;50(2):42-44

Clinical FeaturesTheir characteristics include a persistent circulating CD8 lymphocytosis, diffuse CD8 lymphocytic tissue infiltration with a generalized lymphadenopathy, and parotid gland enlargement.

CD8 lymphocytosis observed in DILS most commonly involves the salivary glands, lungs, liver, kidney, gastrointestinal tract, muscle and peripheral nerve system.

Courtesy : Louis Mandel, David Kim, and Claribel. Parotid gland swelling in HIV diffuse infiltrative CD8 lymphocytosis syndrome.OOO1998;565-569.

Sjogrens syndrome DILS

CD4 cells predominate CD4 cells are diminished, CD8 cells predominate

serum antibodies associated with an autoimmune disease are seen

antibodies are not seen

HyperpigmentationHyperpigmentation of the skin, nails, and mucosa has been reported in HIV-infected patients.

The changes are similar microscopically to focal melanosis, with increased melanin pigmentation observed in the basal cell layer of the affected epithelium.

Several medication s taken by AIDS patients (e.g., ketoconazole,clofazimine, pyrimethamine, zidovudine) may cause theincreased melanin pigmentation.


Hyperpigmentation

Adrenocortical destruction has been reported from several of the infections associated with AIDS, resulting in an Addisonian pattern of pigmentation .

Finally, pigmentation with no apparent cause has arisen in HIV-infected patients, and some investigators have theorized that this may be a direct result of the HIV infection.


Thrombocytopenia

Thrombocytopenia has been reported in nearly 10% of patients with HIV infection andmay occur at any time during the course of the disease.

Some reports show that megakaryocytes have CD4 molecules and may be an additional target for the HIV virus.

Cutaneous lesions are present in most cases, but oral lesions do occur with petechiae, ecchymosis, or spontaneous gingival hemorrhage.


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CD4 count. Journal of Oral Science2011;53(2):203-211.• Iain L C Chapple, John Hamburger. The significance of oral health in HIV disease.

Sex Transm Inf 2000;76:236–243.• WHO Global Health Observatory Data, NACO HIV Data.• Classification and diagnostic criteria for oral lesions in HIV infection. JOPM

1993;22(7): 289-291.• Mithra N. Hegde et al. Oral lesions and immunosuppression in HIV patients.

Biodiscovery 2012 ;(4)3:1-6.• Nicoleta Vaseliu. Oral Manifestations of HIV Infection .

References• Jha R et al.Oral Manifestations of HIV-AIDS: A Diagnostic and Management

Dilemma. Journal of Research in Medical and Dental Science 2014:2(1):96-102.• Louis de Repentigny et al. Immunopathogenesis of Oropharyngeal Candidiasis in

Human Immunodeficiency Virus Infection. CLINICAL MICROBIOLOGY REVIEWS 2004,:17(4)729–759.

• François L. Mayer. Candida albicans pathogenicity mechanisms. Virulence 2013:4(2)119–128.

• Ajay Reginald and B. Sivapathasundharam.. Oral hairy leukoplakia: An exfoliative cytology study. Contemp Clin Dent. 2010 Jan-Mar; 1(1): 10–13.

• Joanne Leger Prasad. Oral hairy leukoplakia in patients without HIV: presentation of 2 new cases. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2014,;118,(5): e151–e160.

• Badari Rao. Kaposi’s sarcoma: Insights into its understanding. International Journal of Contemporary Dental and Medical Reviews (2014), Article ID 031114, 4 Pages.

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References• Gnepp. Diagnostic Surgical pathology of Head and Neck 2nd edition;238-239.• Soujanya Pinisetti. HIV Associated Intra–oral Burkitt’s Lymphoma: A Case Report. J

Clin Diagn Res. 2013 Dec; 7(12): 3088–3089.• Tom Powles, Gail Matthews, Mark Bower. AIDS related systemic non-Hodgkin’s

lymphoma. Sex Transm Inf 2000;76:335–341.• Louis Mandel, David Kim, and Claribel. Parotid gland swelling in HIV diffuse

infiltrative CD8 lymphocytosis syndrome.OOO1998;565-569.

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