Definition

 Lymphoepithelial carcinoma (LEC) is an undifferentiated carcinoma accompanied by a prominent non-neoplastic lymphoplasmacytic infiltrate.

ICD-O code 8082/3

Synonyms

Lymphoepithelioma-like carcinoma (LEC) {1173,1387}; malignant lymphoepithelial lesion {236,2253}; undifferentiated carcinoma with lymphoid stroma {459,2304}; undifferentiated carcinoma {986,1359}; carcinoma ex lymphoepithelial lesion {152}.

 Epidemiology

LEC of the salivary gland is rare, accounting for less than 1% of all salivary gland tumours. It shows a striking racial predilection for Inuits (Eskimo) in the Arctic regions (Greenland, Canada, Alaska), South-eastern Chinese, and Japanese {32,236, 986,1479,1821,2253,2326}. The Inuit populations have the highest worldwide incidence of malignant salivary gland tumours, with the majority represented by LEC {32,236,1708}. Slight female predominance, higher frequency of parotid gland involvement, more frequent high stage disease and apparently more aggressive clinical course have been reported in Inuits {236,1428,1479,1708, 2253,2326,2636}. Patients affected by LEC span a wide age range from the first to the ninth decades, with most cases occurring in the fifth decade. There is a slight male predominance {236}.

 Etiology

 The near 100% association of Epstein- Barr virus (EBV) with salivary gland LEC from the endemic areas, and the presence of the virus in a clonal episomal form suggest an important role of EBV in tumourigenesis {31,236,986,1143,1387, 1428,1479,1821,2636}. Serologic studies show elevated titres of anti-EBV viral capsid antigen IgA or anti-EBV nuclear antigen IgG, though non-specific, in more than 50% of patients with salivary gland LEC from the endemic areas {31,236,1479,2253}. In patients from non-endemic areas, EBV is usually absent, although rare cases may harbour the virus {209,857,1173,1359}. These findings indicate complex interactions of ethnic, geographic and viral factors in the pathogenesis of salivary gland LEC.

 Localization

The parotid gland is affected in approximately 80% of the cases, followed by the submandibular gland {1479,2253,2326, 2636}. LEC can also rarely occur in the minor salivary glands of the oral cavity, oropharynx and hypopharynx.

 Clinical features

 LEC presents as a parotid or submandibular swelling (which may be longstanding with recent rapid increase in size), with or without pain {236,857, 2253}. Advanced tumours may become fixed to the underlying tissues or the skin, although facial nerve palsy occurs in only about 20% of cases. Cervical lymph node involvement, which may be extensive, is seen in 10-40% of cases at presentation {236,1000,1387,1479,2253, 2636}. There is no clinical or serologic evidence of an underlying Sjögren syndrome {1373,1479,2253}. Since LEC of salivary gland is morphologically indistinguishable from nasopharyngeal carcinoma (which is much more common), it is important to examine and biopsy the nasopharynx thoroughly before accepting the salivary gland tumour as primary LEC {377,2252}.

 Macroscopy

The tumours can be circumscribed or show frank invasion into the surrounding  gland and extraglandular soft tissues. They are fleshy and firm, and range from 1-10 cm in size (mean 2-3 cm) {2252}.

Tumour spread and staging

 LEC has a propensity to spread to regional cervical lymph nodes {236, 1479,2636}. Distant metastasis, which can be found in up to 20% of cases at presentation, tends to occur in the lung, liver, bone and brain. In metastatic deposits, the prominent lymphoplasmacytic infiltrate characteristic of the primary lesion may or may not be present.

Histopathology

The tumour grows in infiltrative sheets, islands and cords separated by a lymphoid stroma. The tumour cells possess indistinct cell borders, lightly eosinophilic cytoplasm, oval vesicular nuclei with open chromatin, and conspicuous nucleoli. The nuclei usually show moderate variation in size, although rare cases exhibit fairly uniform-appearing nuclei. Necrosis and mitotic figures are usually easily found. Sometimes the tumour cells can be plump and spindly, with formation of fascicles {445}. Focal squamous differentiation in the form of increased amount of eosinophilic cytoplasm and vague intracellular bridges is occasionally present. The tumour is by definition richly infiltrated by lymphocytes and plasma cells, often accompanied by reactive lymphoid follicles. The lymphoid component can sometimes be so heavy that the epithelial nature of the tumour may not evident. Histiocytes are abundant in the tumour islands in some cases, imparting a “starry sky“ appearance {2253}. Other inconsistent findings are non-caseating granulomas with or without multinucleated giant cells, amyloid deposition {1387}, cyst formation in some tumour islands, perineural and lymphovascular invasion. Tumour cells are immunoreactive for pan-cytokeratin and epithelial membrane antigen. The lymphoid cells include a mixture of B cells and T cells. Electron microscopy shows features of squamous differentiation, with desmosomes and tonofilaments.

In endemic cases, EBV-encoded RNA (EBER) and EBV-DNA can be detected in the tumour cells by in-situ hybridization. Immunohistochemical expression of EBV latent membrane protein 1 is more variable {377,857,986,1316,1479,2326}.

Differential diagnosis

Important differential diagnoses include metastatic undifferentiated carcinoma, malignant lymphoma, lymphoepithelial sialadenitis (no definite cytological atypia, presence of basement membrane-like material, no desmoplastic stroma, no EBV association), lymphadenoma (definite or subtle gland formation, no definite cytological atypia, no desmoplastic stroma, and no EBV association), and large cell undifferentiated carcinoma.

 Precursor lesions

 Most LEC arise de novo but rarely they may develop within lymphoepithelial sialadenitis (formerly myoepithelial sialadenitis) {938}.

Genetic susceptibility

Clustering of salivary gland LEC in family members has been reported {31,91, 1708}. One such family also showed dominantly inherited trichoepitheliomas, suggesting hereditary predisposition related to tumour suppressor genes {1708}.

Prognosis and predictive factors

Five-year survival rate of 75-86% has been reported in patients treated by combined surgery (including neck dissection) and radiation therapy, although local recurrence can occur {236,1387, 1479,2252,2636}. The prognosis is significantly related to tumour stage. There have been attempts to grade LEC based on nuclear pleomorphism and mitotic activity {459,1373}, with suggestion that high-grade tumours are more aggressive, but there are currently no widely accepted or well-validated grading systems.