February 25, 2005
PAROTID ENLARGEMENT in Patient With HIV
Patients with bilateral parotid swellings are seen in the dental office. The swellings may be initiated by HIV. Diagnosis demands a thorough clinical examination combined with imaging. Usually, multiple parotid cysts are present. However, the authors wish to call attention to those HIV patients whose swellings are caused by a lymphocytic infiltration. A case report is used to illustrate signs and symptoms.MULTIPLE ORGAN INVOLVEMENT and symptomatology are the rule in patients with HIV. As can be expected, the oral cavity and its surrounding structures often are targeted by the virus. Head- and neck-related symptoms are seen in 41% of HIV-positive patients at their initial visit,1 with parotid salivary gland enlargement present in 5% to 10% of all HIV patients.23 The parotid involvement is usually bilateral and is associated with cervical lymphadenopathy.
The bilateral parotid swelling is most frequently a reflection of the presence of multiple lymphoepithelial cysts within the gland proper. Occasionally, it reflects an aggressive intraglandular lymphoproliferation. Both processes, the development of cysts and lymphoidal infiltration, are responses to active viral replication within the parotid.4 They probably represent different morphologic manifestations of an exuberant reactive lymphoid hyperplasia.5
Itescu4 et al. have noted that patients with bilateral parotid swelling and cervical lymphadenopathy also have an elevated and persistent circulating CD8 lymphocytosis and a diffuse visceral CD8 lymphocytic infiltration, which frequently cause an interstitial pneumonitis. This symptom complex has been defined as the diffuse infiltrative CD8 lymphocytosis syndrome (DILS),4 and it is considered a subset of HIV patients. DILS patients do not adhere to the standard CD4/CD8 cell depletion scenario. Surprisingly, they have a significant CD8 elevation. Additionally, they seem to have a more favorable prognosis, which appears to be a result of a genetically determined immune response to HIV.4
With the virus infecting increasing numbers of individuals, many positive patients will inevitably be seen in the dental office. It is the purpose of this paper to alert dental professionals to the need to closely scrutinize the parotid glands of their patients to ascertain the possible existence of parotid swelling. Such swellings mandate imaging procedures to determine their nature. In an HIV- positive patient, cysts are usually present, but as stated, the parotid enlargement can also be caused by an intense CD8 lymphocytic infiltration.6,7 This florid lymphoid response may originate from hyperplastic activity of intraparotid lymph nodes, from a proliferation of normally present intraglandular lymphocytes and/or from an extraglandular infiltration into salivary gland tissue.8 Although the salivary gland lymphoproliferation mostly consists of CD8 lymphocytes, 20% to 25% of these T cells are CD4 in lineage, and some are even B cells.9
A 45-year-old HIV-positive female was referred to the Salivary Gland Center (SGC) of Columbia University School of Dental and Oral Surgery. In November 2003, she had sought medical care and was treated with antibiotics for a pulmonary infection. At that time, she was found to be HIV-positive. Upon subsidence of her pulmonary problem, she returned (December 2003) for a consultation regarding bilaterally swollen parotid glands. The infectious disease clinic ordered a CT scan, anticipating the presence of parotid lymphoepithelial cysts. No such cysts were seen. The CT scan report stated that both glands were enlarged with foci of increased density present (Figure 1). In addition, multiple enlarged lymph nodes were seen in the submandibular and cervical areas. Infiltrative changes in the lung were also reported.
The patient was tentatively diagnosed with the oilS variant of HIV after blood studies indicated a CD4 cell count of 445/MM^sup 3^ (normal 390-1770/MM^sup 3^) and an elevated CD8 cell count of 1630/ MM^sup 3^ (normal 240-1200/MM^sup 3^) . Because the CT scan did not visualize the expected pathognomonic cysts, further investigation of the parotid swellings was requested, and the patient was referred to the SGC.
When seen in the SGC (February 2004), the patient, as yet untreated for HIV, was in apparent good health. The patient voiced no complaints associated with her respiratory system. She was concerned about the cosmetic effect of the bilateral parotid swellings, which she said had been present for one year. Questioning indicated that the swellings caused little discomfort, and they did not fluctuate in size during meals.
Extraorally, parotid swellings were obvious with the right parotid larger than the left (Figure 2). Palpation revealed that both parotids were firmer than normal and essentially painless, with a bilateral lymphadenopathy present in both the submandibular triangle and the cervical area.
Intraorally, there were no signs of mucosal pathology. The mucosa was normally moist, with a free salivary flow evident from each parotid duct orifice.
A labial salivary gland biopsy was performed as an aid in ruling out a systemic pathologic process (Sjgreris syndrome, sarcoid) other than DILS. The histologie examination revealed the presence of a mixed chronic inflammatory infiltrate with a marked predominance of lymphocytes (Figure 3). A sialadenitis similar to that seen in Sjgren's syndrome (SS) was noted. It was initially interpreted as a Chisholm grade 3.5, positive for SS.10 Subsequent immunocytochemical findings indicated that the lymphocytic infiltrate was dominated by CD8 cells, thus confirming a diagnosis of DILS. It now could be assumed from the serologic, imaging and histologie evidence that the parotid swellings were caused by a profound CD8 cell infiltration. With this definitive diagnosis, the patient was referred back to her physician for antiviral therapy and care.
Figure 1. CT scan, axial view. Enlarged parotid (P) glands. Most marked on right side.
Figure 2. Clinical view of bilateral parotid swellings (arrows).
Figure 3. Microscopic view of labial gland. Diffuse lymphocytic infiltration (L) replacing glandular mucous acini (A) (Hematoxylin- eosin stain x250).
Clinically bilateral parotid swellings are seen in DILS. Even when the problem is clinically unilateral, imaging usually reveals bilateral involvement. The submandibular salivary gland is only occasionally involved. Our patient did not have the classic parotid cysts associated with HIV, and this created some doubt regarding a DILS diagnosis. Palpation did indicate firmness of both parotids, which probably was a reflection of the massive cellular lymphoidal infiltrate. In turn, the glandular infiltration mirrors and confirms the finding of the elevated circulating CD8 cell count.
Clinically, serology readily differentiates HIV from SS, but the parotid histologic pattern initially can be confused with SS. Differentiation rests in the fact that CD4 cells predominate in SS, while CD8 cells are the dominant feature in the salivary glands of the DILS variant of HIV. Serum counts in the classic HIV-positive untreated patient usually show a decrease in the CD4 cell count with a moderate lowering of the CD8 cells. Because our patient had DILS, a normal level of CD4 cells and an elevation of the CD8 cells were demonstrated. Furthermore, it can be assumed that the pneumonitis seen on the CT scan is representative of the visceral CDS infiltration associated with DILS.
DILS most commonly affects the salivary glands and lungs and, less frequently, the liver, kidney and gastrointestinal tract.4 The salivary glands and lungs contain abundant macrophage lineage cells. It is believed that the preferential CD8 cell infiltration into these locations reflects an immunologic response to the virus within the tissue macrophages.11 The minor salivary glands also have an extensive network of periacinar macrophages that have been shown to be infected with HIV in DILS patients.11 The increased presence of CD8 lymphocytes is likely to have originated in the expanded population of circulating CD8 lymphocytes responding to HIV-related antigens within salivary gland macrophages.11
In any systemic disease that implicates salivary gland tissue, the pathologic process can be expected to include both major and minor salivary glands. In this case, the labial gland histology served to mirror the existing parotid pathology. The accessibility and availability of labial salivary gland tissue make it a readily available diagnostic tool that can be used not only in the diagnosis of DILS, but also for the diagnosis of diverse conditions such as SS and sarcoid.
In the past, management of these parotid enlargements was accomplished by surgical gland removal.12 Today, a successful approach can be achieved with highly active antiretroviral therapy (HAART), a cocktail of viral inhibitors. Therapy with HAART results in cessation of viral replication, a consequent decrease in viral load and a return to more normal CD4/CD8 cell counts. It also has succeeded in eradicating parotid swellings and has become the therapeutic measure of choice.7,13,14 Unfortunately, treatment is lifelong because the immune system cannot totally clear residual virus, and viral rebound can be expected with interruption of therapy.
The natural history of the parotid lymphocytic hyperplasia seen i\n DILS is not fully known. Observation of these patients is mandatory because of the predisposition of HIV patients to develop malignant lymphomas.9,15 Fine-needle aspiration biopsy can serve as an effective diagnostic monitoring procedure.16 Because there were no clinical, radiologie or cytologic indications of malignancy in our patient, observation with periodic fine-needle aspiration biopsy was recommended5,17 in conjunction with HAART.
With the virus infecting increasing numbers of individuals, many positive patients will inevitably be seen in the dental office.
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Louis Mandel, D.D.S.; John Vakkas, D.D.S.
Copyright Dental Society of the State of New York Jan 2005