March 2023 – Cytopathology

A 46-year-old man presented with decreased hearing and feelings of “stuffiness” in his left ear. He was found to have two enlarged lymph nodes in his left neck, both measuring 3 cm. He underwent an FNA of one of the lymph nodes.

Figure 1: Diff-Quick, 40x
Figure 2: Diff-Quick, 100x
Figure 3: H&E, 40x
Figure 4: CK Oscar and p40, 40x
Figure 5: EBV ISH, 40x

What is your diagnosis?

  • Metastatic nasopharyngeal carcinoma
  • Metastatic lymphoepithelial carcinoma
  • Metastatic melanoma
  • Metastatic large cell undifferentiated carcinoma

The correct answer is ...

Metastatic lymphoepithelial carcinoma.

Lymphoepithelial carcinoma (LEC) is a rare, poorly differentiated carcinoma resembling non-keratinizing squamous carcinoma, with an associated prominent nonneoplastic lymphoplasmacytic infiltrate. The malignant cells have large nuclei with prominent nucleoli, and high nuclear-to-cytoplasmic ratios. They can be polygonal with indistinct cell borders. In some cases, the reactive lymphocyte population can equal or appear more prominent than the malignant cells.

Immunohistochemistry (IHC) demonstrates expression of pan-keratin and other squamous markers (i.e., AE1/AE3, ck Oscar, p40, p63, and CK5/6), with no expression for S100, SOX10, CKR7, and CD68. The lymphoplasmacytic infiltrate shows positivity for CD45.

LEC most commonly occurs in the nasopharynx, but can be found throughout the head and neck, including the salivary glands, oral cavity, paranasal sinuses, oropharynx, larynx, esophagus, and lungs. Metastases to regional lymph nodes are more common in salivary LEC, as up to 40% of patients with salivary lesions present with cervical lymph node involvement. Local spread without metastases is more common in sinonasal cases.

Most cases are associated with Ebstein-Barr virus (EBV), and are more common in populations with endemic EBV, such as Southeast Asia and Arctic Inuit communities. The patient in this case was an Asian male. In contrast, in non-endemic populations such as the United States and Japan, EBV association is less common. Of note, while EBV plays an important role in the pathogenesis of this malignancy, it does not appear to be prognostically relevant.

Overall, cases of LEC occur predominantly in men 40-82 years of age, but sex predilection and age of onset differ by primary site. For example, the LEC originating from the salivary gland tends to occur in the fifth decade of life and has a roughly equal prevalence in male and female patients, whereas nasopharyngeal LEC has a higher prevalence in males.

The clinical presentation of LEC varies by location and can include nasal obstruction, epistaxis, facial swelling, neck mass, anosmia, or cranial nerve palsy. Surgical resection and radiation therapy are the primary treatment modalities for this malignancy. The prognosis is similar to squamous carcinoma.


  1. Amit S, Agarwal A, Khan L. Cytomorphological features of lymphoepithelial carcinoma of submandibular gland in an adolescent male. J Cytol 2012;29:216-8. Accessed 14 Jan. 2023. 
  2. Rytkönen, A.E., Hirvikoski, P.P. & Salo, T.A. Lymphoepithelial carcinoma: Two case reports and a systematic review of oral and sinonasal cases. Head and Neck Pathol 5, 327–334 (2011). Accessed 13 Jan. 2023. 
  3. Safneck JR, Ravinsky E, Yazdi HM, Nason RW, Dort JC, Anderson BJ. Fine needle aspiration biopsy findings in lymphoepithelial carcinoma of salivary gland. Acta Cytologica, vol. 41, no. 4, 1997, pp. 1023–1030. PubMed, Accessed 13 Jan. 2023. 
  4. Whaley, R.D., Carlos, R., Bishop, J.A. et al. Lymphoepithelial carcinoma of salivary gland EBV-association in endemic versus non-endemic patients: A report of 16 cases. Head and Neck Pathol 14, 1001–1012 (2020). Accessed 13 Jan. 2023. 
  5. Zidar, N., Gale, N. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: hypopharynx, larynx, trachea and parapharyngeal space. Head and Neck Pathol 16, 31–39 (2022). Accessed 13 Jan. 2023. 

Jane Jarshaw, M.D., M.P.H.

Resident, Anatomic & Clinical Pathology
Mayo Clinic

Charles Sturgis, M.D.

Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education

This post was developed by our Education and Technical Publications Team.