salivary EBV-associated lymphoepithelial carcinoma

Digital cases

 HPC:425 : Salivary EBV-associated lymphoepithelial carcinoma

Definition: Lymphoepithelial carcinoma of the salivary glands is a rare neoplasm that is characterized by a non-neoplastic lymphocytic infiltration associated with an epithelial proliferation. It accounts for approximately 0.4% of all malignant salivary gland tumors.

Lymphoepithelial carcinoma of the salivary gland involves mainly the parotid gland. Racial and geographical factors contribute to the pathogenesis of this tumor.

Lymphoepithelial carcinomas of the salivary gland are rare tumors constantly associated with Epstein-Barr virus (EBV) and mainly identified in Asiatic and Greenlander population.

Because of the relatively limited clinical data concerning LEC of the salivary glands, the clinical course, optimal treatment and prognosis have not been extensively studied.

Lymphoepithelial carcinoma of the salivary gland account for approximately 0.4% of all malignant salivary gland tumors. A limited number of cases were reported from non-endemic areas.

Undifferentiated carcinomas of the salivary glands can be subtyped further into:
 salivary small cell undifferentiated carcinoma
 salivary large cell undifferentiated carcinoma
 salivary lymphoepithelial carcinoma (LEC)

Lymphoepithelial carcinoma (LEC)

Lymphoepithelial carcinoma (LEC) is a specific subtype of undifferentiated carcinoma with characteristic dense lymphoid stroma. The most frequent location is the nasopharynx (UCNT - undifferentiated carcinoma nasophrayngeal type). Identical tumors have been rarely described in the major salivary glands.

Epidemiology

Lymphoepithelial carcinoma (LEC) accounts for approximately 0.4% of malignant salivary gland tumors and has a characteristic extensive and dense lymphoid stroma. This tumor affects the parotid gland in approximately 80% of the cases.

Most cases occur in the fifth decade of life and a predilection for female patients is reported.

There is a racial prevalence in Inuits (Eskimo) in the Arctic region, south-eastern Chinese and Japanese.

Most parotid LEC cases arise de novo, but they may rarely develop within lymphoepithelial sialadenitis. The exact origin and pathogenesis of parotid LEC remains unknown.

Among the possible etiologies are a malignant transformation of the glandular and ductal inclusions in the intra-parotid lymph nodes and a malignant transformation of the epi-myoepithelial island.

In 1991, the presence of EBV was detected by Hamilton-Dutoit et al. in the malignant cells of salivary LECs in the Eskimo population of Greenland.

Only a few cases of EBV-negative LEC have been reported, and almost exclusively in non-Inuit patients suggesting that the virus plays a role in the etiology of LEC.

The association of EBV with salivary gland LEC may also exist in non-endemic areas. It seems there is a complex interaction between genetic factors, environmental factors, and EBV infection in the oncogenic process of LEC of the salivary glands.

Parotid LEC usually presents as an enlarging parotid lump, occasionally painful and with facial nerve involvement in approximately 20% of cases.

Macroscopy

Macroscopically, these tumors are firm, 1–10 cm masses, multinodular, circumscribed, or clearly infiltrative into adjacent salivary gland, fat, muscle, or skin, with a cut surface that varies from a grey-tan to yellow-gray.

Microscopy

Histologically, it is characterized by a syncitial growth pattern and a dense stroma made of non-neoplastic lymphoplasmacytic cells; the lymphoid cells include a mixture of B and C cells and are sometimes associated with germinal centers.

The epithelial component is composed of irregular shaped islands, cords, trabeculae of pleomorphic, large, malignant cells with abundant lightly eosinophilic cytoplasm and vesicular nuclei.

Mitotic rate is variable. Histiocytes are abundant in the tumor islands in some cases, imparting a ‘starry sky’ appearance.3 Other inconsistent findings are non-caseat-ing granulomas with or without multinucleated giant cells and amyloid deposition.

A definite squamous differentiation with intercellular bridges has been identified in several cases.

LEC is indistinguishable from undifferentiated nasopharyngeal carcinoma (UCNT) which is much more common or other LECs that develop in various parts of the body.

Therefore, to confirm the diagnosis of primary LEC in the major salivary glands, metastatic nasopharyngeal carcinoma to the salivary glands should be eliminated through examination of the upper aerodigestive tract with endoscopy and even random biopsy of the nasopharynx.

The parotid gland is the predominant site of occurrence of LEC and an exceptional site of metastasis from nasopharyngeal carcinoma, which more typically metastasizes to the cervical or sub-mandibular lymph nodes.

Differential diagnosis

Histologically, the LEC must be distinguished from benign lesions such as lymphoepithelial sialadenitis and from other epithelial malignancies, such as primary or metastatic poorly differentiated squamous cell carcinoma, adenocarcinoma, and amelanotic melanoma; another differential diagnosis is with large cell or anaplastic types of lymphoma.

Variants

 EBV-associated lymphoepithelial salivary gland carcinoma with EBV-positive low-grade myoepithelial component.(16508782)

Management

The optimal management of LEC of the major salivary glands is complete excision with clear surgical margins followed by adjuvant radiotherapy to the tumor bed and neck.

Neck dissection is reserved for patients who have clinically positive cervical lymph nodes.

Prognosis

Clinical features suggestive of malignancy are rapid-growing course, pain or tenderness, progressive facial nerve palsy and obvious cervical lymphadenopathy.

On presentation, up to 40% of patients have metastases to the cervical lymph nodes, 20% develop local recurrence or lymph node metastases, and 20% have distant metastases within three years following therapy. Distant metastases usually involve the lung, liver, bone, and brain.

Lymphoepithelial carcinoma seems to have a better prognosis than the other undifferentiated carcinomas of the salivary glands, in part because of the lymphoid stroma that has a role in limiting the aggressiveness of this carcinoma.

Advanced disease, the presence of metastases on diagnosis, and histological features such as high mitotic rate, anaplasia, and necrosis are predictors of a worse prognosis.

The 5-year survival rate has been reported to range from 50–87%.

See also

 salivary lymphoid lesions (lymphoid lesions of salivary glands)

Open references

 Salivary gland and nasopharyngeal cancers in individuals with acquired immunodeficiency syndrome in United States. Shebl FM, Bhatia K, Engels EA. Int J Cancer. 2010 May 15;126(10):2503-8. PMID: 19810095 [Free]

 Primary lymphoepithelial carcinoma of the parotid gland in a North African woman. Abdelkrim SB, Trabelsi A, Hammedi F, Omezzine M, Rammeh S, Abdelkader AB, Sriha B. Rare Tumors. 2009 Jul 22;1(1):e16. PMID: 21139887 (Free)

 EBV+ lymphoepithelial carcinoma of the parotid gland in Mexican Mestizo patients with chronic autoimmune diseases. Saqui-Salces M, Martinez-Benitez B, Gamboa-Dominguez A. Pathol Oncol Res. 2006;12(1):41-5. PMID: 16554915 [Free]

 Lymphoepithelial carcinoma versus large cell undifferentiated carcinoma of the major salivary glands. Wang CP, Chang YL, Ko JY, et al. Cancer. 2004;101:2020–7. PMID: 1538947 (Free)

 Lymphoepithelial carcinoma of the submandibular gland—a case report. Jang SJ, Paik SS, Lee WM, Park YW, Jang KJ, Tae K, Lee JD. J Korean Med Sci. 1997 Jun;12(3):252-5. PMID: 9250924 [Free]

 Lymphoepithelial carcinoma of the salivary gland: in situ detection of Epstein-Barr virus. Leung SY, Chung LP, Yuen ST, Ho CM, Wong MP, Chan SY. J Clin Pathol. 1995 Nov;48(11):1022-7. PMID: 8543624 [Free]

References

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 Sporadic EBV-associated lymphoepithelial salivary gland carcinoma with EBV-positive low-grade myoepithelial component. Herbst H, Niedobitek G. Virchows Arch. 2006 May;448(5):648-54. PMID: 16508782

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 Hamilton-Dutoit SJ, Therkildsen MH, Nielsen NH, et al. Undifferentiated carcinoma of the salivary gland in Greenlandic Eskimos: demonstration of Epstein-Barr virus DNA by in situ hybridization. Hum Pathol. 1991;22:811–5.

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 Jang SJ, Paik SS, Lee WM, et al. Lymphoepithelial carcinoma of the submandibular gland – a case report. J Korean Med Sci. 1997;12:252–5.

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 Hsiung CY, Huang CC, Wang CJ, et al. Lymphoepithelioma-like carcinoma of salivary glands: treatment results and failure patterns. Br Radiol. 2006;79:52–5.