FIGURE 19 Aphthous ulcers Source Courtesy of the International AIDS SocietyUSA From Refs 3 4

the color of the surrounding skin or mucosa. Typically asymptomatic, they may become painful when ulcerated and secondarily infected. Oral mucosal lesions are the most common and usually occur in the palate (Fig. 19), gingiva, or lips; they can grow and become bulky, causing mechanical problems or bleeding.

Cutaneous lesions can be seen in the trunk, distal limbs, tip of the nose, and other areas of the head and neck. Due to the location and association with AIDS, they can be aesthetically embarrassing to the patient. The lungs, GI tract, and lymphatic system can also be involved.

KS has been strongly associated with human herpes virus Type 8 (HHV8), also known as KS-associated herpes virus, believed to be transmitted orally.

Diagnosis is made by biopsy. The differential includes purpura, bacillary angio-matosis, hematoma, pyogenic granuloma, and hemangioma.

If treatment is necessary, local excision, topical sclerotherapy, intralesional vinblastine, radiation therapy, or systemic chemotherapy with liposomal doxorubicin or other agents can be given for larger, aggressive lesions or systemic disease. In the HAART era, immune restoration can decrease or eliminate lesions.

Lymphoma. Oral localization of non-Hodgkin's lymphoma might be the initial symptom of this AIDS-defining complication.

Lymphoma can present as diffuse induration, nodule, or ulcers in the oral cavity (Fig. 20), mandibular or maxillary mass, or neck mass from lymph node involvement, but lymphadenopathy may be absent.

The vast majority of HIV-related lymphomas are of B-cell origin and many contain EBV DNA. The most common type is a large B-cell immunoblastic type, followed by Burkitt's, mantle cell, and plasmablastic lymphoma, which is frequently encountered in the oral cavity. OHL has been identified as a predictor of lymphoma. Spontaneous resolution of oral ulcers of lymphoma has been reported, followed by rapid recurrence. Therefore, biopsy of any suspicious oral lesion is recommended, even in the absence of lymphadeno-pathy or B type symptoms (fever, weight loss, malaise, and night sweats).

FIGURE 20 Kaposi's sarcoma of the palate. Source: Courtesy of the International AIDS Society-U.S.A. From Refs. 3,4,11.

FIGURE 20 Kaposi's sarcoma of the palate. Source: Courtesy of the International AIDS Society-U.S.A. From Refs. 3,4,11.

Systemic chemotherapy after referral to an HIV oncology specialist is used in most cases, with varying degrees of prognosis.

A detailed discussion of lymphoma can be found in Chapter 17.

Oral Cancer. Squamous cell carcinoma has not convincingly been associated with HIV; however, cases of oral cancer are reported and the incidence is expected to increase, given prolonged survival in the HAART era.

Idiopathic, Autoimmune, and Other Complications of HIV/AIDS Oral Pigmentation. Reported usually as palatal or buccal hyperpigmented melanotic macules, this HIV-related complication is frequently idiopathic or rarely associated with adrenal insufficiency (Addison's disease), oral zidovudine, or ketoconazole therapy. The exact significance of those idiopathic lesions is unclear.

Recurrent Aphthous Ulcers. Aphthous ulcers of unknown etiology are relatively common in HIV disease, becoming more severe with worsening immunosuppression. Contrary to those found in the general population, aphthous ulcers (canker sores) are often large and not of the minor (herpetiform) type in HIV-infected persons. They can persist for weeks or even months, causing severe pain and disability with resultant malnutrition, which further complicates the problem. Empiric therapy with high-dose acyclovir usually fails. Most often, biopsy and cultures are performed to exclude specific treatable causes such as fungal or viral infection (especially CMV). In most cases, no etiologic agent is found (3). Topical treatment with steroid paste (Lidex) can sometimes be useful, but large lesions require more aggressive management, and oral thalidomide has been tested in clinical trials with very good results in healing these debilitating lesions.

Immune Thrombocytopenic Purpura. Small clusters of purpuric lesions can be found in the oral cavity in HIV-related thrombocytopenia, which can progress to large ecchymoses. Spontaneous bleeding is not uncommon.

Lipohypertrophy and Facial Lipoatrophy. A complication of HIV infection and antiretroviral therapy, loss or accumulation of adipose tissue in the head and neck area has been associated with the introduction of HAART.

Lipohypertrophy usually presents as soft subcutaneous tissue enlargement in the dorsal neck (dorsocervical fat pad) (Fig. 2D) lateral dorsal neck, or other areas. The primary treatment is surgical; open lipectomy combined with aggressive liposuction seems to be required.

Lipoatrophy is usually prominent around the cheeks and lateral frontal areas. This symptom is very embarrassing to many patients and various treatments have been employed. Removing the offending antiretroviral agent can be problematic if no other treatment options exist. Polylactic acid injections (Sculptra®) have been used for treatment, as have silicone implants to enhance the buccal area contour.

Benign Lymphoepithelial Cysts. The most common location is the parotid, probably because of the presence of large lymphoid tissue inclusions within the gland (5); occasionally, lymphoepithelial cysts of the other salivary glands develop. In association with HIV infection, cysts are multiloculated, bilateral in 80% of cases, and contain clear serous liquid. They may need occasional aspiration, for functional or aesthetic reasons. Doxycycline sclerotherapy may prevent recurrence. Secondary infection can occur, usually by Staphylococcus aureus, in which case, incision, drainage, and appropriate antibiotics according to culture report should be prescribed.

Xerostomia. Low salivary flow, reported often as a complication of salivary gland HIV infection, contributes to the infection risk of the periodontal and mucous membranes.

A Sjogren-like syndrome has been described. Saliva substitutes, fluoride applications, aggressive oral hygiene, and low sugar intake are all recommended.

Meth Mouth. Use of crystal methamphetamine has escalated to an epidemic, especially on the West coast of the U.S. Associated xerostomia, bruxism, poor diet and hygiene, the drug itself, and sugar cravings all contribute to rapid dental decay known as "meth mouth."

Salivary Gland Enlargement. Salivary gland enlargement has been associated with HIV infection. The enlargement is usually bilateral and most commonly involves the parotid glands. The glands feel soft, nonfluctuant, and nontender, with diffuse enlargement. Lymphomas can present as discrete unilateral masses within the major salivary glands and are accompanied by regional lymphadenopathy in 10% of cases. Other causes of salivary gland enlargement include CMV, Pneumocystis jirovecii (carinii), adenovirus, KS, tuberculosis, Mycobacterium avium complex (MAC), and sarcoidosis.

Ear and Temporal Bone. External otitis is seen in higher frequency in HIV infection and tends to be more aggressive and often necrotizing [necrotizing external otitis NEO)]. Preexisting external auditory canal dermatitis is common in HIV-related seborrheic dermatitis. The presentation can be atypical with less granulation tissue, and Pseudomonas, Aspergillus, and Proteus are often isolated. NEO can be complicated by temporal bone and skull base osteomyelitis. Most of the cases require hospital admission and parenteral antibiotics. Surgical debridement, as in malignant otitis externa, can be required. External auditory canal polyps from P. jirovecii (carinii) and KS lesions have been reported (5).

Otitis media (OM) in HIV has the same characteristics and pathogenic organisms as in the general population, but higher incidence due to the HIV-related lymphoid hyperplasia and obstruction. OM in HIV can be more often complicated by lateral sinus thrombosis, pseudoaneurysm of the internal carotid, or epidural abscess. OM which is refractory to common treatment or becomes invasive and fistulizing is likely due to mycobacteria or syphilis. OM from Pneumocystis has been reported.

Sensorineural hearing loss (SNHL) may be the first manifestation of AIDS, with a prevalence of about 35%. The causes include CNS infections by HIV (HIV encephalopathy), varicella zoster (Ramsay-Hunt syndrome), syphilis, tuberculosis, P. jirovecii (carinii), C. albicans, S. aureus, Toxoplasma gondii, C. neoformans, CMV, and JC virus. CNS malignancies, depending on location (primary CNS lymphoma, KS, or metastatic disease), can be a cause (23-27). Use of HIV-related ototoxic medications (aminoglycosides, azidothymidine, dideoxyinosine, dideoxycytidine, pentamidine, acyclovir, erythromycin, flucytosine, pyrimethamine, trimethoprim-sulfamethoxazole, amphotericin B, and vincris-tine) can cause sudden or progressive SNHL, vertigo, nausea, and vomiting, or ataxia.

SNHL is discussed in detail in Chapter 28.

Rhinitis and Sinusitis. Nasal congestion in HIV disease can have common causes, including viral or bacterial rhinosinusitis, allergic rhinitis (which is twice as common in HIV as in the general population), or other rhinitis. The common causes of sinusitis (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catar-rhalis) also account for most of the cases in HIV-infected persons. However, in HIV, infectious etiologies also include higher proportions of other gram-positive (S. aureus, Staphylococcus epidermidis, and Propionibacterium acnes), gram-negative (Pseudomonas aeruginosa), fungi (Aspergillus spp., Rhizopus, Alternaria alternata, H. capsulatum, and Scedosporium apiospermum), CMV, mycobacteria, and rarely parasites (cryptos-poridium and microsporidium). Benign lymphoid hypertrophy, fungal or mycobacterial sinusitis, neoplasia (KS, lymphoma), and other causes should be included in the differential in HIV-infected persons (6). Chronic sinusitis, especially fungal sinusitis, can become aggressive and disseminate along perivascular and perineural spaces; in persistent cases, imaging is usually required to look for signs of advancement such as focal bone lysis, obliteration of the periantral fat and of the pterygopalatine fossa, and intracranial spread. Medical therapy consists of hypertonic, pulsatile nasal irrigation, combined with appropriate antibiotic treatment. When medical therapy fails, as is often the case, endoscopic sinus surgery followed by twice-daily nasal irrigations is recommended. Fungal sinusitis is discussed in detail in Chapter 13.

Benign lymphoid hypertrophy is encountered in up to 80% of cases in early HIV infection and can pose a differential diagnosis dilemma for lymphoma. Occasionally, the tissue can be bulky and cause secondary infectious complications such as OM and bacterial sinusitis from obstruction. Imaging will reveal a homogeneous smooth tissue bilaterally filling the nasal cavity and sinuses; biopsy or some degree of debulking might be required for flow cytometry and stains to rule out lymphoma.

KS can involve the nasal cavity and sinuses, presenting with obstruction and epistaxis. Lymphomas commonly involve the nasal cavity and biopsy can provide information on the lymphoma type and guide treatment.

Extranodal sinus histiocytosis (Rosai-Dorfman disease) can present as pedunculated nodules of the nasal cavity, which can cause obstruction and epistaxis, along with systemic signs and symptoms of bilateral cervical lymphadenopathy, low-grade fevers, leukocytosis, anemia, hypergammaglobulinemia, and an elevated erythrocyte sedimentation rate (6). Diagnosis is made by biopsy and management is expectant since spontaneous resolution might occur.

Larynx and Trachea. The larynx can be involved in bacterial (bacillary angiomatosis), mycobacterial (tuberculosis), fungal (candidiasis, histoplasmosis, and coccidioidomycosis), viral (HSV, varicella zoster virus (VZV), and HPV), and neoplastic (KS, lymphomas, and carcinomas) complications in HIV disease. Clinical presentations are described for each entity, but hoarseness, odynophagia, dysphagia, blood-streaked sputum, frank hemoptysis, and aspiration can be common manifestations of laryngeal and tracheal involvement. The otorhinolaryngologist should take respiratory precautions when examining a patient to avoid the risk of dissemination, especially of laryngeal TB or papilloma virus. Bacillary angiomatosis, and to a lesser extent, KS lesions, can bleed profusely if biopsied.

Esophagus. Other than candidiasis, HSV, and CMV, the esophagus can be involved in histoplasmosis and can be a site for KS, lymphoma, and squamous cell carcinoma. Idiopathic esophageal ulcers are described both in the chronic latent phase and in PHI. Esophageal motility disorders are common in HIV disease.

Neck Lymphadenopathy and Masses. Cervical lymphadenopathy affects 50% of HIV patients. The posterior cervical lymphatic chains are most commonly involved. When there is no obvious focus of infection, the differential diagnosis (Table 2) between reactive nodes, infected nodes, and neoplastic nodes is not always clear. When fine needle aspiration (FNA) fails to secure a diagnosis, open biopsy is indicated.

Special note should be made of two entities, which are encountered relatively often or exclusively in HIV infection.

Multicentric Castleman's Disease. Multicentric Castleman's disease (20) is a rare lymphoproliferative disorder, strongly associated with HHV8, the virus implicated in KS pathogenesis. The disease clinically presents with generalized malaise, night sweats, rigors, fever, anorexia, and weight loss; on physical examination, lymphadenopathy, hepatosplenomegaly, ascites, edema, and pleural as well as pericardial effusions predominate. Laboratory investigations may reveal thrombocytopenia, anemia hypoalbuminemia, and hypergammaglobulinemia. Treatment options are debated and include cytotoxic

TABLE 2 Differential Diagnosis of Lymphadenopathy in HIV Disease Without an Obvious Primary Focus

Differential diagnosis of HIV-related lymphadenopathy

Acute HIV infection

Lymphoma

Tuberculosis

Mycobacterium avium complex and atypical mycobacteria

Immune reconstitution inflammatory syndrome

Kaposi's sarcoma

Histoplasmosis

Coccidioidomycosis

Castleman's disease

Syphilis

Epstein-Barr virus Cytomegalovirus Tularemia Sarcoid chemotherapy, immunotherapy with interferon or rituximab, and antivirals such as ganciclovir or foscarnet. Prognosis is poor.

Immune Reconstitution Inflammatory Syndrome. Immune reconstitution inflammatory syndrome (IRIS) presents as an adverse effect of HAART, usually within 8 to 12 weeks of initiation of treatment. It is believed to be due to immune restoration due to HAART, and intensification of the inflammatory reaction to a preexisting OI. Occasionally in IRIS, a new OI may present in the initial months of HAART treatment. Associated OIs can be tuberculosis (where paradoxical reactions after initiation of HAART have been seen even after many months of treatment), MAC disease, CMV end organ disease, hepatitis B or C flares, etc. Clinically, patients may present with fever, diffuse lymphadenopathy, and worsening of OI symptoms.

Although radiographic imaging can assist with diagnosis of lymphadenopathy since intense contrast enhancement suggests nodal increased vascularity, e.g., an acute infection, KS, and lymphomas, there is a definite need for excisional biopsy if FNA is not diagnostic.

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