Malignant lymphoepithelial lesion of the parotid gland: A case report and review of the literature. (Original Article).

Abstract

Malignant lymphoepithelial lesions are rare tumors of the major salivary glands. They most often occur in Asians and Greenland Eskimos and are strongly associated with Epstein-Barr virus infection. We report a case of a malignant lymphoepithelial lesion of the parotid gland that developed in an Italian-American woman whose serology was positive for Epstein-Barr virus antibody. The patient underwent a left total parotidectomy and upper neck dissection, followed by radiation therapy. At the 2-year follow-up, she remained free of disease.

Introduction

Malignant lymphoepithelial lesions (MLELs) are rare tumors of the major salivary glands that occur most often in Asians and Greenland Eskimos. According to several serologic, immunohistochemical, and in situ hybridization studies, MLELs are strongly associated with Epstein-Barr virus (EBV) infection. (1) In this article, we report a case of MLEL of the parotid that developed in an Italian-American woman whose serology was positive for EBV antibodies.

Case report

A white 54-year-old woman of Italian descent was referred to us for evaluation of a slowly enlarging, painless, nontender left parotid mass of 5 months' duration. She denied any history of radiation exposure, facial weakness, cervical lymphadenopathy, or recent fever, tooth extraction, or trauma. Her medical and surgical history was significant for benign breast masses and a hysterectomy for a leiomyoma. Her family history was significant in that her brother had undergone a left parotidectomy 1 month earlier for removal of a salivary gland tumor, which proved to be a mucoepidermoid carcinoma.

On physical examination, a 2.5-cm mass was found in the left parotid. Her facial nerve function was intact, and no enlarged cervical lymph nodes were palpated. A detailed examination of the nasopharynx and Waldeyer's ring, which included fiberoptic nasopharyngoscopy, found no lesions.

Magnetic resonance imaging (MRI) detected a 4 x 1.9 x 1.7-cm dumbbell-shaped mass in the deep lobe of the left parotid (figure 1). The long axis was oriented in the craniocaudal direction and was interpreted as most likely representing a pleomorphic adenoma. No pathologic nodes were identified. The size of the right parotid was within normal limits.

Analysis of a fine-needle aspiration biopsy sample at an independent laboratory revealed a moderately cellular specimen of cytologically benign non-neoplastic salivary parenchyma in a background of mature lymphocytes. Small clusters of oncocytic cells were observed. The cytologic findings suggested the presence of either an inflammatory process, Warthin's tumor, or a low-grade, mixed-cellularity, lymphoproliferative disorder.

The patient underwent a left total parotidectomy and upper neck dissection with preservation of the facial nerve. Pathology revealed a poorly differentiated carcinoma with abundant lymphoid infiltrate. The epithelial component was made up of large cells with abundant granular eosinophilic cytoplasm. The nuclei contained open chromatin material with prominent nucleoli. The lymphoid component was made up of small, mature lymphocytes (figure 2). The surrounding parotid tissue was normal. One lymph node was positive for tumor. Based on these findings, a diagnosis of MLEL of the parotid was made.

EBV antibody titers were analyzed, including EBY capsid antibody IgG (negative), EBNA-IgG antibody (positive), and EBV EA antibody (positive). These findings were consistent with a late convalescent stage of EBV infection.

The patient underwent postoperative radiation therapy. A total of 6,120 cGy was delivered to the site of the left parotid and 5,400 cGy to the lower neck. At the 2-year follow-up, the patient remained free of disease.

Discussion

MLEL was first described by Hilderman et al in 1962. (2) Since then, another 105 cases (including ours) have been reported in the English-language literature. Most of these reported cases have occurred in Asians and Eskimos. Overall, there is a female preponderance, as the male-to-female ratio is 2-to-3; however, among Chinese patients, the tumor is more prevalent in males.

MLEL involves only the major salivary glands, most often the parotid; about 15% of cases involve the submandibular gland. (3) Morphologically, MLEL resembles lymphoepithelioma (undifferentiated nasopharyngeal carcinoma with lymphoid stroma), and it is often difficult to distinguish MLEL from metastatic nasopharyngeal carcinoma of the salivary gland. (3) Lymphoepithelioma of the nasopharynx is most often seen in patients from southern China. Lymphoepithelioma-like carcinoma has been reported at sites other than the salivary glands, including the thymus, stomach, lung, skin, larynx, floor of the mouth, uterine cervix, tonsil, and sinonasal tract. (4) These tumors are often found in non-Asian patients, and their EBV titers have been consistently negative. (1) EBV has been proven to be strongly associated with lymphoepithelioma of the nasopharynx, salivary gland, and thymus.

MLEL tumors can be either infiltrative with indistinct borders, partially circumscribed, or multinodular. The cut surfaces are firm and pinkish-white. These tumors frequently metastasize to parotid, cervical, and retroauricular nodes and occasionally to supraclavicular and peritracheal nodes. (3,5) Distant metastases are also not uncommon, particularly those to the lung, liver, and bone. (5)

Histology confirms the infiltrative nature of the tumor, which often features an indistinct demarcation from the surrounding salivary tissue. The tumor is made up of irregular islands of neoplastic malignant epithelial cells in a sea of small mature lymphocytes. These islands have been likened to pieces of a jigsaw puzzle. (3) The epithelial cells have indistinct borders and eosinophilic granular cytoplasm. The nuclei are crowded and generally oval or irregularly shaped; they feature a vesicular or coarse chromatin pattern, often with one or two prominent eosinophilic nucleoli. Focal spindle cell elements have been reported only rarely. (6) A definite squamous differentiation with intercellular bridges has been identified in several cases. (3) The presence of mitoses is variable. The dense infiltrate of lymphocytes and plasma cells often extends into the residual salivary gland parenchyma.

Microscopically, the differential diagnosis of MLEL includes benign lymphoepithelial lesion, metastatic undifferentiated carcinoma (especially of the nasopharynx), anaplastic carcinoma, poorly differentiated squamous cell carcinoma, and malignant lymphoma. With the exception of metastatic undifferentiated nasopharyngeal carcinoma, most of these diagnoses can be determined with meticulous microscopic examination and immunostaining. Before a diagnosis of MLEL of the salivary gland can be made with certainty, careful fiberoptic nasopharyngoscopy and/or analysis of random biopsies of the nasopharynx and Waldeyer's ring should be performed to rule out metastatic disease.

The origin and pathogenesis of MLEL is still unknown. Among the possible etiologies that have been hypothesized are a malignant transformation of the epimyoepithelial island (7) and a malignant transformation of the glandular and ductal inclusions in the intraparotid lymph nodes. (8)

The strong association between MLEL and EBV suggests that the virus has a role in the etiology of MLEL. (3) Many studies have found that EBV was present in the malignant epithelial islands in patients with MLEL. The Center for Infectious Diseases (part of the Centers for Disease Control and Prevention) has even reported that EBV is specific to the tumor. (9) Only a few cases of EBV-negative MLEL have been reported, most of them in non-Eskimo patients. (8) It has been suggested that EBV infects the primitive pharynx and transforms the epithelial cells, leading to a clonal expansion of these cells. These epithelial cells then form a lymphoepithelioma-like carcinoma that is histologically indistinguishable in the nasopharynx, salivary glands, and thymus. However, the absence of EBV in lymphoepithelioma of the palatine tonsil, which is also derived from the primitive pharynx, suggests that other factors (e.g., environmental or genetic predisposition) are involved in the pathogenesis of the tumor. We still do not know why EBV causes (1) lymphoepithelioma of the nasopharynx in Eskimos and southern Chinese, (2) MLEL of the parotids in Greenland Eskimos, (3) MLEL of the submandibular glands in Asians, and (4) Burkitt's lymphoma in Africans.

Treatment of MLEL requires surgery and, in some cases, postoperative radiation therapy. Five-year survival has been reported to range from 70 to 85%. (3) In patients with advanced disease that features anaplastic epithelial cell islands and metastasis, 2-year survival is poor despite treatment. (3)

References

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(2.) Hilderman WC, Gordon JS, Large HL, Carrol CF. Malignant lymphoepithelial lesion with carcinomatous component apparently arising in parotid gland. A malignant counterpart of benign lymphoepithelial lesion? Cancer 1962;15:606-10.

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(5.) Abdulla AK, Mian MY. Lymphoepithelial carcinoma of salivary glands. Head Neck 1996;18:577-81.

(6.) Christiansen MS, Mourad WA, Hales ML, Oldring DJ. Spindle cell malignant lymphoepithelial lesion of the parotid gland: Clinical, light microscopic, ultrastructural, and in situ hybridization findings in one case. Mod Pathol 1995;8:711-5.

(7.) Batsakis JG, Bemacki EG, Rice DH, Stebler ME. Malignancy and the benign lymphoepithelial lesion. Laryngoscope 1975;85:389-99.

(8.) Kountakis SE, SooHoo W, Maillard A. Lymphoepithelial carcinoma of the parotid gland, Head Neck 1995;17:445-50.

(9.) Lanier AP, Clift SR, Bornkamm G, et al. Epstein-Barr virus and malignant lymphoepithelial lesions of the salivary gland. Arctic Med Res 1991;50:55-61.