Resident Program - Case of the Month

Diagnosis:

C.) Lymphoepithelial carcinoma (LEC) is an undifferentiated carcinoma with a solid, syncytial growth pattern and a dense, non-neoplastic lymphoid infiltrate.  In addition to the characteristic morphology mentioned in the previous “Microscopic Description” section, LEC may also exhibit squamous differentiation, spindle cell features, and basaloid features.  Tumors are typically mitotically active and may contain areas of necrosis.  Immunohistochemical (IHC) stains show expression of cytokeratins.  Positivity for p63 may be present with variable reactivity.

LEC is associated with Epstein-Barr virus (EBV), especially in endemic areas.  If present, detection can be done by EBV-encoded RNA by in situ hybridization (EBER ISH).  While most LEC are related to EBV, only a minority of cases in western populations is positive for EBV, as seen in this case.

Most LEC develop de novo but it has been postulated that they may arise through malignant transformation of benign lymphoepithelial lesions or glandular inclusions in intraparotid lymph nodes.  An association between LEC and autoimmune disorders such as Sjögren syndrome is unclear.

LEC accounts for less than one percent of salivary gland malignancies, most often arise in the parotid gland, and is more common in North American Eskimo peoples, indigenous peoples of Greenland, Southeast Asians, Japanese, and Northern Africans.  Most patients present in the fifth to sixth decade of life.  Nodal metastases and distant metastases occur in up to 40 percent and 10 to 20 percent, respectively, of patients with LEC.  The 5-year overall survival rate is reported to be approximately 70 to 80 percent.

Differential Diagnosis:

A.) Nasopharyngeal carcinomas (NPC) arise from the nasopharyngeal mucosa and exhibit squamous differentiation.  They are comprised of three major types: non-keratinizing nasopharyngeal carcinoma (NK-NPC), keratinizing nasopharyngeal carcinoma (K-NPC), and basaloid squamous cell carcinoma (BSCC).

NK-NPC can be difficult to differentiate from LEC due to their very similar morphology, including a prominent non-neoplastic lymphoid infiltrate.  As a result, a complete clinical and radiological evaluation should be performed to exclude the possibility of metastatic NK-NPC.  There was no evidence of primary nasopharyngeal disease in this case.  Furthermore, while LEC is also associated with EBV, NK-NPC is positive for EBV in almost all cases.  The lack of positive staining by EBER ISH in this case lends support against NK-NPC.

K-NPC shows obvious squamous differentiation, including the presence of intercellular bridges and keratinization, and is accompanied by desmoplasia.  BSCC consists of pleomorphic tumor cells with hyperchromatic nuclei and scant cytoplasm, among other morphologic features typical of similar tumors in other head and neck sites.  A prominent lymphoid infiltrate may not be present in K-NPC or BSCC.  The morphologic differences between LEC, K-NPC, and BSCC are often sufficient to distinguish them apart.

In general, NPC stain strongly for IHC markers of squamous differentiation such as p63 and p40.  The tumor presented in this case was negative for p40, which would be unexpected for NPC.

B.) Large cell lymphoid neoplasms with similar morphology to LEC can be distinguished in large part by IHC.  Unlike LEC, lymphoid neoplasms are usually positive for hematopoietic lineage markers such as CD45 and negative for cytokeratins such as AE1/AE3 in the tumor cells.  The opposite staining pattern was demonstrated in the tumor presented in this case.

D.) Large cell neuroendocrine carcinoma is a poorly differentiated carcinoma that may share overlapping morphologic features with LEC.  However, this tumor typically shows neuroendocrine differentiation and expresses associated IHC markers such as synaptophysin.  The tumor presented in this case was negative for synaptophysin.

References:

1. El-Naggar AK, Chan JK, Grandis JR et al. WHO Classification of Head and Neck Tumours.  IARC Who Classification of Tum; 2017.
2. Ambrosio MR, Mastrogiulio MG, Barone A, et al. Lymphoepithelial-like carcinoma of the parotid gland: a case report and a brief review of the western literature.  Diagn Pathol.  2013;8:115.
3. Schneider M, Rizzardi C. Lymphoepithelial carcinoma of the parotid glands and its relationship with benign lymphoepithelial lesions.  Arch Pathol Lab Med.  2008;132(2):278-82.
4. Wenig BL. Lymphoepithelial Carcinoma.  ExpertPath.  https://app.expertpath.com/document/lymphoepithelial-carcinoma/f2b421bd-1387-4ecb-93b8-63ba5253f2e9.  Updated March 8, 2018.  Accessed April 9, 2020.