What is nonkeratinizing squamous cell carcinoma?


Nonkeratinizing squamous cell carcinoma (NKSCC) is a type of cancer made up of squamous cells. Squamous cells are thin, flat cells that normally cover the surface of the skin and line many internal areas of the body, including the mouth, throat, lungs, cervix, and anal canal.

In healthy tissue, squamous cells often go through a process called keratinization, where they produce a strong protein called keratin. Keratin makes the cells tougher and more resistant to damage. In NKSCC, the cancer cells do not produce significant amounts of keratin. Under the microscope, this makes them look different from squamous cells that undergo keratinization.

Where in the body is nonkeratinizing squamous cell carcinoma found?

Nonkeratinizing squamous cell carcinoma can arise in any of the following body sites:

  • Oropharynx (tonsils, base of the tongue, and soft palate).

  • Nasopharynx (the area behind the nasal passages, where it is called nasopharyngeal carcinoma).

  • Sinonasal tract (nasal cavity and sinuses).

  • Lungs.

  • Cervix.

  • Anal canal.

What are the symptoms of nonkeratinizing squamous cell carcinoma?

The symptoms of NKSCC depend on where the tumor develops.

  • Oropharynx (tonsils, tongue base, soft palate): Persistent sore throat, trouble swallowing, ear pain, or a lump in the neck.

  • Nasopharynx: Nasal congestion, frequent nosebleeds, hearing loss, ear pain, or neck swelling.

  • Sinonasal tract: Blocked or congested nose, nosebleeds, facial pain, swelling around the eyes, or repeated sinus infections.

  • Lungs: Persistent cough, shortness of breath, chest pain, coughing up blood, or unexplained weight loss.

  • Cervix: Irregular vaginal bleeding, pain or discomfort during sex, or unusual discharge.

  • Anal canal: Bleeding, pain, discomfort, or a lump around the anus.

What causes nonkeratinizing squamous cell carcinoma?

The causes of NKSCC vary depending on the part of the body affected.

  • Human papillomavirus (HPV): Most cases in the oropharynx, cervix, and anal canal are caused by infection with high-risk types of HPV.

  • Epstein-Barr virus (EBV): EBV infection is strongly linked to NKSCC in the nasopharynx.

  • Tobacco smoking: Smoking is a major cause of NKSCC in the lungs.

In many cases, viral infections such as HPV or EBV lead to long-lasting genetic changes in squamous cells, eventually causing them to become cancerous.

How is this diagnosis made?

The diagnosis of NKSCC is usually made after a biopsy. In a biopsy, a doctor removes a small piece of tissue from the suspicious area. A pathologist examines the sample under the microscope to look at the size, shape, and arrangement of the cells.

What does nonkeratinizing squamous cell carcinoma look like under the microscope?

Under the microscope, NKSCC is made up of sheets, nests, or clusters of abnormal squamous cells. The cells are usually medium to large in size with round to oval nuclei (the control centers of the cells). The nuclei often look darker than normal and may contain one or more visible nucleoli (small structures where proteins are made).

Unlike keratinizing squamous cell carcinoma, there are no obvious keratin pearls or thick layers of keratin on the surface of the tumor. Instead, the tumor cells have a smoother appearance and may show frequent mitotic figures, which are signs of rapid cell division.

Why is it called “nonkeratinizing”?

The term “nonkeratinizing” refers to the lack of keratin production by the tumor cells. In other types of squamous cell carcinoma, the cells make keratin, which forms round, pink structures under the microscope called keratin pearls. These are not seen in NKSCC. Because the cancer cells do not go through keratinization, the tumor is classified as nonkeratinizing.

Other tests that may be performed to confirm the diagnosis

Immunohistochemistry (IHC)

IHC is a test that uses antibodies to look for specific proteins in the tumor cells. It can help confirm that the tumor is made of squamous cells and may provide information about viral involvement.

  • p16: Often positive in HPV-related tumors, especially in the oropharynx, cervix, and anal canal.

  • Cytokeratins (CK5/6, CK7, CK20): Proteins that help show the type of squamous cell carcinoma and rule out other cancers.

  • EBV-related markers (EBER by ISH): Used when nasopharyngeal carcinoma is suspected.

Molecular tests

Molecular tests look for changes in the DNA or RNA of the tumor cells.

  • In situ hybridization (ISH): Detects viral DNA or RNA from HPV or EBV directly in tumor cells.

  • Polymerase chain reaction (PCR): A sensitive test to confirm the presence of HPV or EBV genetic material.

  • Next-generation sequencing (NGS): May be performed in some cases to identify genetic changes that help guide treatment, especially in tumors of the lung.

These additional tests confirm the diagnosis and sometimes influence treatment decisions, such as whether immunotherapy or targeted therapy may be helpful.

Questions to ask your doctor

  • Where in my body is the nonkeratinizing squamous cell carcinoma located?

  • Was my tumor associated with HPV or EBV?

  • Were immunohistochemistry or molecular tests performed, and what were the results?

  • What treatment options are available for this type of cancer?

  • Does the nonkeratinizing nature of the tumor affect my treatment or prognosis?

  • What stage is my cancer, and what does that mean for me?

A+ A A-