Indian Journal of Dental Research

: 2011  |  Volume : 22  |  Issue : 5  |  Page : 688--697

Orofacial manifestation of hematological disorders: Hemato-oncologic and immuno-deficiency disorders

Titilope A Adeyemo, Wasiu L Adeyemo, Adewumi Adediran, Abd Jaleel A Akinbami, Alani S Akanmu 
 Departments of Haematology and Blood Transfusion And Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Nigeria

Correspondence Address:
Titilope A Adeyemo
Departments of Haematology and Blood Transfusion And Oral and Maxillofacial Surgery, College of Medicine, University of Lagos


The aim of this paper is to review the literature and identify orofacial manifestations of hematological diseases with special reference to hemato-oncologic, immuno-deficiency disorders, and human immunodeficiency virus infection. A computerized literature search using MEDLINE was conducted for published articles on orofacial manifestations of hematological diseases with emphasis on hemato-oncologic and human immunodeficiency virus (HIV) infection. Mesh phrases used in the search were: Oral diseases AND hematological disorders; orofacial diseases AND leukemias; orofacial lesions AND lymphomas; orofacial diseases AND multiple myeloma, orofacial manifestations AND HIV. The Boolean operator DQANDDQ was used to combine and narrow the searches. The full texts of these articles were thoroughly examined. References in these articles also were manually searched non-Medline articles. Only relevant articles were selected for the review. Orofacial manifestation of malignant hematological diseases may present as primary clinical features due to infiltration of orofacial tissues, or as secondary due to the subsequent infiltration of normal bone marrow elements, or tertiary due to the side effects of the treatment. HIV-associated orofacial lesion may be a clinical indicator of HIV infection in otherwise healthy, undiagnosed individuals; an early clinical feature of HIV infection; clinical markers for the classification and staging of HIV disease or may be a predictor of HIV disease progression. Orofacial manifestations of malignant hematological diseases and HIV infection are not uncommon findings in clinical practice. These manifestations may be clinical indicators of hematologic disorders in otherwise healthy, undiagnosed individuals.

How to cite this article:
Adeyemo TA, Adeyemo WL, Adediran A, Akinbami AA, Akanmu AS. Orofacial manifestation of hematological disorders: Hemato-oncologic and immuno-deficiency disorders.Indian J Dent Res 2011;22:688-697

How to cite this URL:
Adeyemo TA, Adeyemo WL, Adediran A, Akinbami AA, Akanmu AS. Orofacial manifestation of hematological disorders: Hemato-oncologic and immuno-deficiency disorders. Indian J Dent Res [serial online] 2011 [cited 2014 Apr 20 ];22:688-697
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Full Text

A number of systemic diseases including hematologic disorders do have manifestations in the orofacial region. [1] This can been attributed to the fact that the oral cavity is thought to be the window to the body, and the face, the most prominent part of the body. [1] Although non-pathognomonic, these manifestations may often represent the initial sign of the underlying hematopoietic disease. [2]

In the first part of 2-part series of articles on orofacial manifestation of hematological disorders, [3] orofacial manifestations of anemia (iron deficiency anemia, Plummer-Vinson syndrome, megaloblastic anemia, sickle cell anemia, thalassemia and aplastic anemia) and hemostatic disorders (von Willebrand's disease, hemophilia, and idiopathic thrombocytopenic purpura) were discussed.

This is the final part of a 2-part series of articles on orofacial manifestations of hematological disorders. The aim of this paper is to review the literature and identify orofacial manifestations of hematological diseases with special reference to hemato-oncologic and immune deficiency disorders as well as human immunodeficiency virus infection.

 Orofacial Manifestations of Malignant Hematological Disorders

Acute leukemias

Leukemias are the most common neoplastic diseases of the white blood cells with an incidence of 9 per 100.000 of the population. [4] The risk of developing acute leukemia in children under the age of 10 years is estimated to be 1 in 2.500. [4] The general characteristics of acute leukemias include uncontrolled proliferation of undifferentiated or poorly differentiated hematopoietic stem cells and the subsequent accumulation of the malignant cells in the bone marrow with suppression of normal hematopoietic elements. The main symptoms are due to the lack of normal red blood, white blood cells and platelets, as well as to the circulation of blast cells in the peripheral blood and their accumulation in various extramedullary tissues such as the lymph nodes and the spleen. [4] All types of leukemia, especially the acute leukemias, may present with signs and symptoms in the orofacial region [Table 1]. [5],[6],[7] Acute monoblastic/monocytic leukemia and acute myelo-monocytic leukemia (according to the WHO classification for myeloid malignancies), commonly present with signs and symptoms in the oral cavity. Reported incidence of oral manifestations in leukemias varies from 18% to 80%. [5],[6],[7],[8],[9] Stafford et al.[6] found that oral manifestations were more common in patients with acute leukemia compared to chronic leukemia. It was reported that 65% of the patients with leukemia had some form of oral pathology, especially mucosal bleeding as the initial presentation. [6] {Table 1}

The orofacial manifestations of acute leukemia are well documented and relate closely to the underlying pathogenesis of the disease [Table 1]. They can be subdivided into primary, secondary, and tertiary manifestations. [2] The primary manifestations frequently include lesions caused by the extramedullary neoplastic infiltration of oral mucosal and maxillofacial tissues such as generalized or localized gingival enlargement, chloroma, alveolar bone destruction, bone invasion with pain and tooth displacement, cervical lymphadenopathy, tooth ache due to the leukemic infiltration of the pulp and leukemia cutis. [2],[5],[6],[7],[8],[9],[10],[11],[12],[13] Gingival swelling with partial or total coverage of the crowns of the teeth is a common feature especially in acute monocytic leukemia and is thought to be, at least partly, the result of gross infiltration of the gingiva by blast cells. The increased tendency to oral bleeding predisposes to impaired oral hygiene and accumulation of microbial plaque and debris, which in combination with the pre-existing local factors, acts as an inflammatory stimulus for an exaggerated response to plaque with subsequent reactive connective tissue hyperplasia of the gingival soft tissues and accelerated periodontal destruction. [14],[15]

Neurologic manifestations such as facial paralysis, trigeminal neuralgia, inability to protrude the tongue, difficulty in swallowing, weakness in biting and paraesthesia or anesthesia of the face, lips or tongue may also be signs of acute leukemia and are due to increased cerebrospinal fluid pressure, intracranial hemorrhage, or localized leukemic infiltration of the central nervous system or around the peripheral nerves. [16] Less frequently, mental nerve neuropathy, called "numb chin syndrome," may be the presenting complaint. [17]

Secondary oral manifestations of leukemia include signs due to the suppression of normal hematopoietic bone marrow (anemia, leucopoenia, thrombocytopenia) such as generalized mucosal pallor, non-specific oral erythema or cyanosis, erosions and usually painful or even necrotic ulcerations caused by small vessels thrombosis from leukemic cells or by the diminished local immune response. [13],[14],[16] Spontaneous prolonged and profuse mucosal bleeding or after trivial trauma, as well as petechiae, ecchymosis, and hematoma are usually observed. [2],[5],[6],[7],[8],[9],[10],[11],[12],[13]

The prevalence rate of 77% is reported for gingival hemorrhage that relates to thrombocytopenia associated with acute leukemia. [4] Neutropenic mucosal ulcerations are found in 49% of leukemic patients and this occurs with values less than 1000 neutrophils/mm. [4]

Increased susceptibility to viral, fungal, and bacterial infections or reactivation of latent infections such as osteomyelitis, pericoronitis, periodontal, or periapical persistent and prominently painful inflammations are frequent signs. [5],[6],[7],[8],[9],[10],[11],[12],[13] Oral candidiasis, primary or secondary herpetic gingivostomatitis, acute necrotizing ulcerative gingivitis, impaired healing responses e.g. after tooth extraction, hairy leukoplakia, and multiple viral warts are also observed. [5],[6],[7],[8],[9],[10],[11],[12],[13] Palatal ulcerations and necrosis may herald the presence of mucormycosis of the nasal cavity and the paranasal sinuses in patients with acute leukemia. [18]

Tertiary manifestations of leukemia occur due to the toxicity of chemo- or radiotherapy (e.g. oral mucositis, xerostomia, bacterial, fungal, and viral infections) or to graft versus host disease after allogeneic bone marrow transplantation (e.g. xerostomia, lichenoid reactions). Radiation therapy usually precedes bone marrow transplant in leukemic patient. [19] The effects of radiation and chemotherapy in the oral cavity are well known and extremely common. [19] Radiation delivered to the head and neck region for either primary or secondary malignancies may produce mucositis as well as atrophy of the salivary glands, usually with the serous acinar glands being more affected than the mucous acinar glands, leading to a syndrome of xerostomia similar to Sjögren's syndrome. [19] Patients receiving radiation to the head and neck have a high incidence of radiation caries due to a change in the pH of the oral cavity, radiation-induced xerostomia, and increasing cariogenic organisms (Lactobacillus and Streptococcus mutans), and a definite breakdown of the periodontal membrane, with subsequent radiation induced cervical caries. [20] Radiation caries may be significantly prevented by the use of pre-treatment fluoride gels. [20] Other chronic changes caused by radiation therapy include radio-osteonecrosis of the mandible or maxilla. [21] Chemotherapy for systemic malignancies can also produce a variety of changes in the oral cavity - ranging from stomatitis to gangrene - often with little surrounding secondary inflammation. [22] Stomatitis, an inflammatory and rather painful reaction, is seen with a variety of chemotherapeutic agents, most often with cytosine arabinoside, methotrexate, cyclophosphamide, anthracycline derivatives, 5-fluorouracil, and bleomycin. [22] Chemotherapy can also produce changes in the salivary glands similar to those attributed to radiation therapy, with intense xerostomia. The effects of chemotherapy are also manifested through myelosuppression and immunosuppression. [22] The immunosuppressive effects of chemotherapy, especially prednisolone, can result in oral candidiasis and reactivation of herpes simplex virus (HSV) leading to oral mucositis. [23] Oral mucositis can also occur from chemotherapy without an HSV component, since thinning of the surface layer of mucosa and/or bone marrow suppression allows for opportunistic organisms to invade the mucosa. This may be prevented or attenuated by maintenance of meticulous oral hygiene and use of topical antimicrobial agents. [23]

Chronic graft-versus-host disease (cGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT) and a major cause of morbidity and mortality. [24] Oral involvement of cGVHD occurs in 80% to 100% of patients suffering from cGVHD and may be an early manifestation of this complication contributing significantly to the overall burden of the disease. [24],[25] Oral cGVHD lesions closely resemble those seen with a number of autoimmune connective tissue disease including lupus erythematosus and Sjögren's syndrome. [24],[25] Mucosal erythema, atrophy, and ulceration are often noted clinically with lichen planus-like lesions being the most distinctive oral lesion. Superficial mucoceles and salivary gland changes including changes in both flow rate and sialochemistry are also often seen. [24]

Other miscellaneous oral signs and symptoms in patients with acute leukemia include poor oral hygiene, sore throat, laryngopharyngitis, dysphagia, dry and cracked lips in febrile patients, hairy tongue, sialorrhea, halitosis, cacogeusia, benign migratory glossitis, median romboid glossitis, para-neoplastic pemphigus, and eruption hematoma. [6],[7],[26]

Sixteen per cent and 8% of children with acute leukemia are reported to have gingivitis and mucositis, respectively. [27]

Acute lymphoblastic leukemia may involve the lymphoid-bearing tissue of the orofacial region including the tonsils. Intraorally, mucosal pallor, gingival bleeding, or ecchymoses may be seen, while lymphadenopathy of the head and neck region is a consistent sign. [8],[9] Pericoronitis may also be an initial manifestation of acute lymphoblastic leukemia. [28] The etiology is usually attributable to local factors. Katz and Peretz [29] reported trismus as the first presentation of an acute lymphoblastic leukemia in a 6-year-old boy, when intraoral examination and panoramic radiograph demonstrated no signs of infection and/or other pathology. The trismus could be explained as an intensive infiltration of leukemic cells into the deep portion of the contracting muscles of the face. This case emphasizes the importance of physical examination and independent judgment made by dentists, even when patients are referred to them by other members of the medical communities.

Chronic lymphocytic leukemia and malignant lymphomas

Chronic lymphocytic leukemia particularly has the proclivity to involve the tonsillar tissues as well as other lymphoid-bearing soft tissues in the oral mucosa. [5],[30] Purpura and gingival bleeding secondary to thrombocytopenia may also be seen. [5],[30]

Non-Hodgkin's lymphomas (NHL) of various histologic types, including Burkitt's lymphoma are the third most common group of malignant lesions in the oral cavity and maxillofacial region including the soft palate and Waldeyer's ring following carcinomas and sarcomas. [31] Most of such lymphomas have been shown to be predominantly of B-cell lineage. [31] Eisenbud et al., [31] in a review of this subject, revealed that in 31 cases of initial oral presentations of non-Hodgkin's lymphoma, 75% were diffuse non-Hodgkin's lymphoma, and 13 out of the 31 (on subsequent staging) were either stage III or IV. Clinically aggressive lymphomas, such as Burkitt's lymphoma, diffuse large B-cell lymphoma, and NK-/T-cell lymphomas particularly display major predilection for symptomatic involvement of the bony maxilla or mandible and are characterized by destruction of the maxilla, mandible, and bones around the paranasal sinuses, which is indistinguishable from bony destruction in other malignant tumors of the jaws. [32]

Oral manifestations of NHL are rarely primary, most often representing a secondary sign of a widespread disease and they appear as soft, diffuse, asymptomatic swellings with overlying ulceration affecting mainly the tonsils, the palate, the buccal mucosa, the gingiva, the tongue, the floor of the mouth, the salivary glands, and the retromolar region [Table 1]. [32] Alveolar bone loss with swelling and pain that mimics a periodontal inflammation, numbness of the lip, and pathologic fractures are common signs of jaw involvement. [31],[33],[34],[35],[36],[37],[38] In rare cases, paraneoplastic pemphigus of the oral mucosa has been seen in association with NHL. [39]

Burkitt's NHL, a type of high-grade, small noncleaved, follicular center cell lymphoma is predominantly an extranodal disease particularly affecting the jaws, ovaries, and the gut, but involvement of the cervical lymph nodes and the bone marrow has also been reported. [40] In Africa, Burkitt's lymphoma accounts for 50% of all childhood malignancies with an average age at onset of 7 years and a 2:1 male predominance. [2] The disease is predominantly extranodal with jaw involvement as the single most common initial site, while spread to the surrounding oral soft tissues and parotid gland as well as involvement of the abdominal viscera (retroperitoneum, kidneys, liver, ovaries, endocrine glands) are also commonly seen. [40],[41] The tumor most often initially arises in the posterior region of the maxilla spreading subsequently to all four quadrants and result in an increased teeth mobility, intra-oral masses [Figure 1], pain, paraesthesia of the lip and toothache due to the infiltration of the pulp, especially of the developing teeth [Table 1]. Radiographically, a moth eaten poorly marginated radioluscency is often observed, while the bone cortex may be expanded, eroded, or perforated by soft tissue infiltration [Figure 2]. [41],[42] {Figure 1}{Figure 2}

Mycosis fungoides, a form of cutaneous T-cell lymphoma in which the skin is involved initially with a psoriaform or eczematous lesions that progress to plaques with tumor formation, may remain localized to the skin for many years, with only late involvement of the internal organs. [43],[44],[45] The oral mucosa is rarely involved, but may present as a late feature, and very rarely as the initial manifestation of the disease. Erythematous areas or white plaques, which may show central necrosis and nonspecific ulcerations, are the main oral signs of mycosis fungoides. [43],[44],[45]

Hodgkin's lymphomas do also manifest in the oral cavity particularly in the palate, floor of the mouth, and gums. [46],[47],[48],[49],[50] Although Hodgkin's disease involving the oral cavity is considered a rarity, several cases have been described in the soft tissues, as well as in the mandible and maxilla. [46],[47],[48],[49],[50] Occasionally, the oral manifestations may present as the initial and the only sign of disease, while in other cases cervical lymphadenopathy with or without more widespread disease may be present at the same time. [50] In the oral cavity tonsillar enlargement, usually unilateral may be present in early phases and when extranodal sites are involved, submucosal swellings may be observed on the gingiva, the tongue or the buccal mucosa accompanied by mucosal ulcerations, as well as erosions of the underlying bone. [49],[50]

Myeloproliferative disorders

Chronic myeloid leukemia (CML) which is one of the myeloproliferative disorders is most commonly seen in adults at the age between 30 and 50 years. [4] CML accounts for about 20% of all cases of leukemia. Affected patients develop hepatosplenomegaly, with massive enlargement of the spleen due to infiltration by leukemic cells. The peripheral blood shows leukocytosis with an excess of neutrophils, myelocytes, and metamyelocytes. [4] Oral sign occurs rarely and are mainly associated with the suppression of normal bone marrow in the accelerated phase of the disease, with the exception of granulocytic sarcoma of the jaws, which is a rather common finding, observed during the chronic phase of the disease. [51],[52] It represents a localized deposit of myeloid cells having a whitish or a green tinge color due to the production of myeloperoxidase. [52]

Myelofibrosis is a disease that is also in the myeloproliferative category, either secondary to the spent phase of polycythemia rubra Vera or as a primary process. [53] It is a cause of chronic anemia, which after many years may also present with masses in the mandible and maxilla. A biopsy will reveal extramedullary hematopoiesis. [53]

Polycythemia, either primary (caused by malignant involvement of the bone marrow and a part of the myeloproliferative syndromes) or secondary (caused by hypoxemia of various etiologies), can often present with engorged reddish-purple discoloration of the gingiva and tongue, petechiae, and ecchymoses, while spontaneous gingival bleeding may be rarely seen. [54]

Myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by ineffective hemopoiesis leading to refractory cytopenias and qualitative abnormalities of one or more lineages. [55] MDS are more common in the late adult life and may progress to leukemia in 40% of cases. [55] The main problem is an indolent anemia due to the ineffective hemopoiesis that requires treatment with transfusions. [55],[56] Clinically, patients may show mucosal pallor, weakness, and exertion-dyspnea. Persistent, recurrent mucosal ulcerations, gingival bleeding, and an increased susceptibility to viral, fungal, and bacterial infections of the oral cavity due to the compromised immune dysfunction, is frequent in MDS patients. [55],[56]

Multiple myeloma

Multiple myeloma (MM) and, its counterpart, amyloidosis are both caused by malignant proliferation of plasma cells (differentiated B cells). Orofacial signs and symptoms are not uncommon in MM and oral manifestations are the first sign of the disease in about 12-15% of the patients. [57],[58] Orofacial manifestation occurs in 14% of patients with MM. [57] These lesions include swellings in the jaws and soft tissue masses resembling epulis caused by extramedullary plasmacytomas, gingival hemorrhage, odontalgia, pain (usually related to radiolucent areas of myeloma in the mandible or maxilla), xerostomia, numbness, and labial anesthesia (secondary to nerve compression by bony masses, amyloid nodules, or extramedullary plasmacytomas). Involvement of bone can produce root resorption and mobility and migration of the teeth, jaw radioluscency, and pathologic fractures. [59],[60],[61] Osteolytic lesions of the jaws resulting from osteoclastic activation by cytokines, may be involved in 30% of cases. [57],[61],[62],[63]

MM results in immunosuppression; therefore, a variety of oral infections may be present in MM patients. These include oral hairy leukoplakia and candidiasis. [64],[65] Amyloid deposits in the tongue can also lead to macroglossia with smooth atrophic tongue or, more commonly, appearing as pearly papules on the tongue and oral mucosa. [66]

Effects of the myeloma proteins on coagulation factors and platelet aggregation, thrombocytopenia secondary to myelophthisic involvement of the bone marrow by plasmacytosis, and the effects of chemotherapy can all produce oral petechiae or hemorrhagic bullae. [67] These may resemble either immunologic thrombocytopenic purpura or hemophilia. [67]

Langerhans' cell histiocytosis (histiocytosis X)

Langerhans' cell histiocytosis (LCH) represents a spectrum of clinical disorders ranging from a highly aggressive and frequently fatal leukemia-like disease affecting infants to a solitary lesion of bone. [68] LCH can also occur in adolescents and adults. Oral manifestations include large irregular ulcerations of the hard palate, gingiva, and floor of the mouth, along with a necrotizing gingivitis which may be the primary manifestation of the disease, ecchymoses, periodontitis, and subsequent tooth loss. [68] Ulcerated nodules, difficulty in chewing, and foul-smelling breath also occur. Oral swellings or ulcerations resulting from mandibular or maxillary bone involvement are common. Of the bones of the jaw, the mandible is the most frequently involved. [69] Oral lesions may occur without underlying bone destruction. In these rare cases, ulceration of the palate or gingiva may be the primary oral sign. [69]

Radiolucent bone lesions can occur anywhere but are most common in flat bones, such as the posterior jaw. [70] Radiologic findings demonstrate rapid progressive alveolar bone loss with dental extrusion, producing the characteristic appearance of "floating teeth." These lesions result in fractures and displaced teeth. [70] The presence of alveolar bone loss in young children with precocious exfoliation of primary teeth should suggest the possibility of LCH. [70]

Orofacial manifestation of immune deficiency disorders

Immunodeficiency resulting from defect in neutrophil number or function is commonly associated with orofacial lesions. Two qualitative defects in granulocytes that are associated with oral manifestations are Chronic granulomatous disease and Chédiak-Higashi disease. Chronic granulomatous disease is an inherited metabolic defect in the oxidative killing of organisms by normal-appearing granulocytes having the ability to phagocytize but not to kill. [71] These patients are afflicted with recurrent bacterial infections with chronic suppurative cervical lymphadenitis. They can also present with recurrent aphthous-like ulcers in the mouth. [71]

The second disorder Chédiak-Higashi disease, an inherited disease of the lysosomal membrane of granulocytes, is characterized by large blue lysosomal particles in white cells demonstrated with Wright's stain. Partial cutaneous albinism and defects in platelet and coagulation function are other features. Patients with this disease also suffer from recurrent bacterial infections and can present with periodontal disease and mouth ulcerations. [72]

Human immunodeficiency virus infection/acquired immune deficiency syndrome

Since HIV infection was first described in 1981, a variety of orofacial conditions associated with HIV disease have been documented. Orofacial manifestation is an indication of a progressive decline in immune function in HIV-infected patients. Studies have shown that 70% to 90% of people infected with HIV will develop at least one oral manifestation during the course of the disease. [71],[72],[73],[74] A review of the literature shows that HIV-associated orofacial lesions have been considered as:

Clinical indicators of HIV infection in otherwise healthy, undiagnosed individuals. [75],[76]Early clinical features of HIV infection. [77],[78],[79]Clinical markers for the classification and staging of HIV disease. [79]Predictors of HIV disease progression. [80],[81],[82]

Oral cavity is easily accessible to clinical examination; hence, orofacial lesions associated with HIV infection may be used as clinical markers of HIV disease progression. [74] There are two main classification systems of oral lesions associated with HIV infection. The first is based on the etiology of the oral lesions. According to this system, lesions are classified as bacterial, viral, or fungal infections or neoplastic lesions or other conditions. [74],[83] The second, more widely used system, recommended by the EC Clearing house 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. [84],[85] [Table 2] show the classification of orofacial lesions associated with HIV/AIDS in adults. [85] {Table 2}

Oral candidiasis frequently associated with Candida esophagitis is the most common orofacial manifestation of HIV infection. [85] Its prevalence may depend on study population, diagnostic criteria, study design, and availability of antiretroviral therapy. Reported prevalence rates have varied widely, up to 72% in children and 94% in adults. [72],[74],[78],[85] Oral candidiasis has also been shown to be a significant predictor of HIV disease progression in both adults and children. [86] The median time of survival from its clinical diagnosis to death has been reported as 3.4 years among HIV-infected children. [86]

Oral candidiasis occurs in four clinical forms: [87],[88] pseudomembranous candidiasis, erythematous (atrophic) candidiasis, hyperplastic candidiasis, and angular cheilitis. Pseudomembranous candidiasis (oral thrush) is characterized by the presence of multiple superficial, creamy white plaques that can be easily wiped off, revealing an erythematous base. [87] They are usually located on the buccal mucosa, oropharynx, and/or dorsal face of the tongue. Erythematous (atrophic) candidiasis is a less common atrophic form of candidiasis seen as patches on the palate, mucosa, or tongue; this form is much more difficult to diagnose. [88] It appears clinically as multiple small or large patches, most often localized on the tongue and/or palate. In hyperplastic candidiasis, the so-called candida leukoplakia the lesions appear white and hyperplastic and cannot be removed by scraping but they do regress with treatment. [88] It can be confused with other forms of leukoplakia and it is a rare form of oral candidiasis in HIV-infected persons. [88] Angular cheilitis is characterized by the presence of erythematous fissures at the corners of the mouth. It is usually accompanied by another form of intra-oral candidiasis. [88]

Other orofacial fungal infections that have been seen in AIDS patients include histoplasmosis, which must be diagnosed by biopsy and requires systemic therapy, geotrichosis, which can be diagnosed by culture or potassium hydroxide preparation and requires amphotericin therapy, aspergillosis and cryptococcosis, which can be cultured or biopsied and, again, requires amphotericin therapy. [81],[87],[88],[89]

Herpetic gingivostomatitis is another frequent oral infection. Herpes simplex (HSV) infection is a very common viral syndrome in AIDS patients and may either be primary (herpetic gingivo-stomatitis) or secondary (herpes labialis). [85] The prevalence of oral HSV infection varies between 10% and 35% in adults and children with HIV infection. [72],[74],[85] The presence of HSV infection for more than 1 month constitutes an AIDS-defining condition. [85] It can usually be diagnosed by clinical appearance or in smears and usually can be readily controlled by oral acyclovir. [85] Herpes zoster ophthalmicus is also a frequently seen facial and ocular lesion. Most patients with herpes zoster ophthalmicus present with a periorbital vesicular rash distributed according to the affected dermatome with a minority of patients developing conjunctivitis, keratitis, uveitis, and ocular cranial-nerve palsies. [90] Permanent sequelae of ophthalmic zoster infection may include chronic ocular inflammation, loss of vision, and debilitating pain. [90]

Hairy leukoplakia is usually grouped with viral infections and has been described in all risk groups for AIDS in patients with HIV infection. Oral hairy leukoplakia (OHL) is an oral infection caused by Epstein-Barr virus (EBV). [91] It presents as white, thick patches that do not wipe away and that may exhibit vertical corrugations with a "hair-like" appearance. [72],[74] The lesions usually start on the lateral margins of the tongue and sometimes inside the cheeks and lower lip and may spread across the entire dorsal surface, onto the ventral surface of the tongue, and occasionally may be found on buccal mucosa. It may be unilateral or bilateral. [72],[74] OHL is often associated with oral candidiasis and is more common among HIV-infected adults than among HIV-infected children. [78],[85] The reported prevalence of OHL in adults is about 20-25% and increases as the CD4+ lymphocyte count decreases, whereas in children the prevalence is about 2-3%. [72],[74],[78],[85] The presence of OHL is a sign of advanced immuno-suppression (CD4 count <200 cells/mL) and has been described as a significant predictor of HIV disease progression in adults. [92] The differential diagnosis of OHL includes Candida leukoplakia, epithelial dysplasia (oral cancer), which is also common in these patients, and the white sponge nevus, a plaque form of lichen planus. [92]

Periodontal (gum) disease is also common among HIV-infected patients. It is characterized by bleeding gums, bad breath, pain/discomfort, mobile teeth, and sometimes sores. Its reported prevalence ranges widely, between 0% and 50%. [72],[74],[85] Left untreated, HIV-associated periodontal disease may progress to life-threatening infections, such as Ludwig's angina and noma (Cancrum oris). [72],[74] Four forms of HIV-associated periodontal disease have been described: [93] Linear gingival erythema, necrotizing ulcerative gingivitis, necrotizing ulcerative periodontitis (NUP), and necrotizing stomatitis. Linear gingival erythema (LGE) is characterized by the presence of a 2-3 mm red band along the marginal gingiva, associated with diffuse erythema on the attached gingiva and oral mucosa. The degree of erythema is disproportionately intense compared to the amount of plaque present on the teeth. [93] Necrotizing ulcerative gingivitis (NUG) is more common in adults than in children. It is characterized by the presence of ulceration, sloughing, and necrosis of one or more interdental papillae, accompanied by pain, bleeding, and fetid halitosis. [93] NUP is characterized by the extensive and rapid loss of soft tissue and teeth. This disease is usually rapidly progressive with loss of periodontal soft tissue and rapid destruction of supporting bone with loss of teeth. [93] The disease may be so fulminating as to resemble noma seen in severely malnourished patients in developing countries. [93] Necrotizing stomatitis is thought to be a consequence of severe, untreated NUP. It is characterized by acute and painful ulcero-necrotic lesions on the oral mucosa that exposes underlying alveolar bone. There have been reports of oro-nasal fistulae developing. [93]

Recurrent aphthous ulcers (RAUs) occur in about 1-7% of HIV-infected patients. [72],[74],[85] They are painful ulcers on the non-keratinized oral mucosa, such as labial and buccal mucosa, soft palate, and ventral aspect of the tongue. Severe recurrent aphthous lesions usually occur when the CD4+ lymphocyte count is less than 100 cells/mm 3 . The etiology of RAUs is not well known. RAUs may present as minor, major, or herpetiform aphthae. [72],[74],[85] Minor aphthous ulcers are ulcers less than 5 mm in diameter covered by pseudomembrane and surrounded by an erythematous halo. They usually heal spontaneously without scarring. Major aphthous ulcers resemble minor aphthous ulcers, but they are fewer and larger in diameter (1-3 cm), are more painful, and may persist longer. Their presence interferes with mastication, swallowing, and speaking. Healing occurs over 2 to 6 weeks. Scarring is very common. Herpetiform aphthous ulcers occur as a crop of numerous small lesions (1-2 mm) disseminated on the soft palate, tonsils, tongue, and/or buccal mucosa.

Parotid enlargement is commonly associated with HIV infection in children (10-30%), and less commonly in adults. [72],[85] It has been shown to occur in the late course of HIV infection and to be associated with a slower rate of HIV disease progression. The median time from its diagnosis to death has been reported to be 5.4 years among HIV-infected children. [86] Lymphocytic infiltration of the salivary glands may be an etiologic factor. Parotid enlargement occurs as unilateral or bilateral swelling of the parotid glands. It is usually asymptomatic but may be accompanied by decreased salivary flow (xerostomia). Problems with dry mouth in HIV-infected patients are often caused by medications that interfere with salivary secretion, such as antihistamines, anti-anxiety medications, antidepressants, and some antiretroviral drugs (didanosine and zalcitabine). [75],[94] Treatment is required only in severe cases and may consist of systemic analgesics, anti-inflammatory, antibiotics, and/or steroids.

The incidence of oral warts due to human papillomavirus (HPV) infection has increased dramatically since the advent of HIV infection. The lesions are more prevalent in adults (1-4% of cases) than in children. [72],[74],[85] Oral warts may appear cauliflower-like, spiked, or raised with a flat surface. The most common clinical presentation is multifocal flat lesions resembling focal epithelial hyperplasia (Heck's disease). [95] The most common location is the labial and buccal mucosa.

HIV-associated malignant lesions

Kaposi's sarcoma and lymphomas are well-known AIDS defining lesions and occurrence in orofacial region have been reported. [96],[97] Kaposi's sarcoma, the cell of origin being the endothelial cell, was once a very rare disease. It is now closely linked with AIDS and involves plaque like lesions of the skin, which on biopsy are often diagnosed as sclerosing hemangiomas. KS is the most common tumor in HIV-infected patients, and is considered an AIDS-defining illness by the guidelines of the Centers for Disease Control (Atlanta, GA). [97] The incidence rate of 3.3% of KS has been reported in HIV-infected patients. [98] The most common extracutaneous sites are oral cavity, gastrointestinal tract, and lung. Oral cavity KS may be the first manifestation of HIV infection. [96] The most common intraoral site of involvement is hard palate, followed by gingiva. Other potential sites of involvement are soft palate, tongue, tonsils, floor of the mouth, and pharynx. While most oral cavity disease is asymptomatic, it may be bulky or ulcerated and affect oral intake or speech. [97]

AIDS-related lymphomas can develop in intraoral sites or salivary glands far more frequently than in HIV-negative persons. Lymphomas, especially the non-Hodgkin's variant, are classified as one of the lesions strongly associated with HIV infection. [85] HIV-associated extranodal non-Hodgkin's lymphomas of orofacial region have been reported. [99],[100] Typical sites within the mouth are palate or gingiva, where the tumors form soft painless swellings which ulcerate when traumatized. [72] Burkitt's lymphoma is 1000 times more common than in HIV-negative persons in Western world. [72]


Orofacial manifestations of malignant hematological diseases and immunodeficiency disorders are not uncommon findings in clinical practice. Orofacial manifestations of malignant hematological diseases may present primarily with clinical features due to infiltration of oral soft and hard tissues, or as secondary to the subsequent infiltration of bone marrow elements, or tertiary to the side effects of treatment. Qualitative defects in granulocytes are also associated with oral manifestations; presenting with recurrent aphthous-like ulcers and periodontal disease. HIV-associated orofacial lesion may be a clinical indicator of HIV infection in otherwise healthy, undiagnosed individuals, an early clinical feature of HIV infection, clinical markers for the classification, and staging of HIV disease or may be a predictor of HIV disease progression.


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