Non-keratinizing squamous cell carcinoma of the lung

by Jason Wasserman MD PhD FRCPC
March 27, 2024

Non-keratinizing squamous cell carcinoma of the lung is a type of non-small cell lung cancer (NSCLC). The term “non-keratinizing” means that this particular type of cancer does not show the typical keratin pearl formation or extensive keratinization that is often observed in the more common keratinizing squamous cell carcinoma. Non-keratinizing squamous cell carcinoma typically arises in the central parts of the lungs, often in association with a history of smoking.

What causes non-keratinizing squamous cell carcinoma of the lung?

The most common cause of non-keratinizing squamous cell carcinoma of the lungs is long-term exposure to cigarette smoke.

What are the symptoms of non-keratinizing squamous cell carcinoma of the lung?

Symptoms of non-keratinizing squamous cell carcinoma of the lung include persistent or worsening cough, coughing up blood, chest pain, and shortness of breath. Tumours that have spread to other parts of the body may cause additional symptoms depending on the location in the body. For example, tumours that metastasize (spread) to bones may cause bone pain and can cause the bone to break. Doctors describe this as a pathologic fracture.

How is this diagnosis made?

The initial diagnosis of non-keratinizing squamous cell carcinoma of the lung is usually made after a small sample of tissue is removed in a procedure called a biopsy or a fine needle aspiration (FNA). Surgery may then be performed to remove the entire tumour. The type of surgery performed to remove the tumour will depend on the size of the tumour and its location in your lung. A wedge resection is usually performed to remove small tumours and those near the outside of the lungs. Lobectomies and pneumonectomies are performed for large tumours or those that are near the centre of the lungs.

Your pathology report for non-keratinizing squamous cell carcinoma of the lung

Your pathology report for non-keratinizing squamous cell carcinoma of the lung depends on the type of procedure performed. Your pathology report after a small procedure such as a fine needle aspiration biopsy (FNAB) may provide only the diagnosis and the results of tests used to confirm the diagnosis such as immunohistochemistry (IHC). After a larger surgical procedure to remove the tumour, your pathology report may include additional information such as the tumour size, spread through air spaces, pleural invasion, and margins. If any lymph nodes were removed, they will be described as well. Molecular tests may be performed to look for genetic changes in the tumour and those results may be included in the biopsy report or after the tumour is removed. All of these topics are discussed in greater detail in the sections below.

Microscopic features of non-keratinizing squamous cell carcinoma of the lung

When examined under the microscope, non-keratinizing squamous cell carcinoma is made up of large, dark blue cells. The cells appear blue because they have not undergone keratinization, a process where the cells produce and store large amounts of a protein called keratin. When present, keratin is normally found in the cytoplasm (body) of the cell and it gives the cell a pink colour. The tumour cells also tend to show a range of shapes and sizes which pathologists describe as pleomorphic. Numerous mitotic figures (tumour cells dividing to create new tumour cells) are also usually seen.

Immunohistochemistry

Your pathologist may perform a test called immunohistochemistry to confirm the diagnosis. This test helps differentiate non-keratinizing squamous cell carcinoma from other types of lung tumours such as adenocarcinoma and large cell neuroendocrine carcinoma that can look similar under the microscope. The results will be described as positive (reactive) or negative (non-reactive).

Non-keratinizing squamous cell carcinoma of the lung usually shows the following results:

• p40 – Positive.
• CK5 – Positive.
• TTF-1 – Negative.
• Chromogranin – Negative.
• Synaptophysin – Negative.

Multiple tumours

It is not uncommon for more than one tumour to be found in the same lung. When this happens, each tumour will be described separately in your report.

There are two possible explanations for finding more than one tumour:

1. The tumour cells from one tumour have spread to another part of the lung. This explanation is more likely when all of the tumours are of the same histologic type. For example, if all of the tumours are non-keratinizing squamous cell carcinomas. If the tumours are on the same side as the body, the smaller tumours are called nodules. If the tumours are on different sides of the body (right and left lung), the smaller tumour is called a metastasis.
2. The tumours have developed separately. This is the more likely explanation when the tumours are of different histologic types. For example, one tumour is a non-keratinizing squamous cell carcinoma while the other is an invasive adenocarcinoma. In this situation, the tumours are considered separate primaries and not metastatic disease.​

Pleural invasion

Pleural invasion refers to the spread of cancer cells into the pleura, which is the thin layer of tissue that surrounds the lungs and lines the inside of the chest cavity. There are two layers of the pleura: the visceral pleura, which sticks to the lungs, and the parietal pleura, which lines the chest wall and diaphragm. Pleural invasion by lung cancer means that the tumour has grown beyond the lung tissue itself and into the surrounding pleural layers.

Pleural invasion is important both for determining the pathologic stage and for prognosis:

• Tumour stage: The presence of pleural invasion is a significant factor in determining the stage of lung cancer. Tumours that invade the pleura are considered more advanced than those confined to the lung parenchyma (the functional tissue of the lung). According to the TNM classification system used for staging lung cancer, pleural invasion may increase the T category of the tumour, which signifies tumour size and extent. For example, a tumour that invades the visceral pleura might be classified as T2, while invasion into the parietal pleura or involvement of pleural effusion (fluid accumulation) could lead to a higher classification.
• Prognosis: Patients with lung cancer that has invaded the pleura generally have a poorer prognosis than those without pleural involvement. This is because pleural invasion reflects a more aggressive tumour that is more likely to spread and cause complications, such as pleural effusion, which can impair lung function and lead to symptoms like chest pain, cough, and shortness of breath.

Lymphovascular invasion​

Lymphovascular invasion refers to the spread of cancer cells into a blood vessel or lymphatic channel. Blood vessels are long thin tubes that carry blood around the body. Lymphatic channels are similar to small blood vessels except that they carry a fluid called lymph instead of blood. The lymphatic channels connect with small immune organs called lymph nodes that are found throughout the body. Lymphovascular invasion is important because once inside a blood vessel or lymphatic space, cancer cells can spread to lymph nodes or other parts of the body such as the liver or bones.

Margins

​In pathology, a margin is the edge of a tissue that is cut when removing a tumour from the body. The margins described in a pathology report are very important because they tell you if the entire tumour was removed or if some of the tumour was left behind. The margin status will determine what (if any) additional treatment you may require.

Pathologists carefully examine the margins to look for tumour cells at the cut edge of the tissue. If tumour cells are seen at the cut edge of the tissue, the margin will be described as positive. If no tumour cells are seen at the cut edge of the tissue, a margin will be described as negative. Even if all of the margins are negative, some pathology reports will also provide a measurement of the closest tumour cells to the cut edge of the tissue.

A positive (or very close) margin is important because it means that tumour cells may have been left behind in your body when the tumour was surgically removed. For this reason, patients who have a positive margin may be offered another surgery to remove the rest of the tumour or radiation therapy to the area of the body with the positive margin.

Lymph nodes

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to lymph nodes through small vessels called lymphatics. For this reason, lymph nodes are commonly removed and examined under a microscope to look for cancer cells. The movement of cancer cells from the tumour to another part of the body such as a lymph node is called metastasis.

Lymph nodes from the neck, chest, and lungs may be removed at the same time as the tumour. These lymph nodes are divided into areas called stations. There are 14 different stations in the neck, chest, and lungs (see picture below).

If any lymph nodes were removed from your body, they will be examined under the microscope by a pathologist and the results of this examination will be described in your report. Most reports will include the total number of lymph nodes examined, where in the body the lymph nodes were found, and the number (if any) that contain cancer cells. If cancer cells were seen in a lymph node, the size of the largest group of cancer cells (often described as “focus” or “deposit”) will also be included.

The examination of lymph nodes is important for two reasons. First, this information is used to determine the pathologic nodal stage (pN). Second, finding cancer cells in a lymph node increases the risk that cancer cells will be found in other parts of the body in the future. As a result, your doctor will use this information when deciding if additional treatment such as chemotherapy, radiation therapy, or immunotherapy is required.

Pathologic stage (pTNM)

​The pathologic stage for non-keratinizing squamous cell carcinoma of the lung is based on the TNM staging system, an internationally recognized system created by the American Joint Committee on Cancer. This system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. In general, a higher number means a more advanced disease and a worse prognosis.

Tumour stage (pT)

The pathologic tumour stage for non-keratinizing squamous cell carcinoma is based on the size of the tumour, the number of tumours found in the tissue examined, and whether the tumour has broken through the pleural or has spread to organs around the lungs.

Nodal stage (pN)

The pathologic nodal stage for non-keratinizing squamous cell carcinoma is based on the presence or absence of cancer cells in a lymph node and the location of the lymph nodes that contain tumour cells.

• NX – No lymph nodes were sent for pathologic examination.
• N0 – No tumour cells were found in any of the lymph nodes examine
• N1 – Tumour cells were found in at least one lymph node from inside the lung or around the large airways leading into the lung. This stage includes stations 10 through 14.
• N2 – Tumour cells were found in at least one lymph node from the tissue in the middle of the chest and around the large airways. This stage includes stations 7 through 9.
• N3 – Tumour cells were found in the neck or in any lymph nodes on the side of the body opposite (contralateral) to the tumour. This stage includes stations 1 through 6.

About this article

Doctors wrote this article to help you read and understand your pathology report. Contact us if you have questions about this article or your pathology report. For a complete introduction to your pathology report, read this article.

Other helpful resources

Atlas of pathology