Non-Keratinizing Squamous Cell Carcinoma of the Lung: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 29, 2026

Non-keratinizing squamous cell carcinoma (NKSCC) is a subtype of squamous cell carcinoma of the lung — a cancer that belongs to the group known as non-small cell lung cancer (NSCLC). The term “non-keratinizing” means that the cancer cells do not produce visible amounts of a structural protein called keratin. This is what makes it different from keratinizing squamous cell carcinoma, in which the cancer cells produce keratin that can be seen under the microscope as distinctive structures called keratin pearls. Because non-keratinizing squamous cell carcinoma lacks these visible features, the pathologist must use specialized protein tests to confirm the squamous identity of the tumor. In all other important respects — how it is treated, how it behaves, and what the pathology report describes — non-keratinizing squamous cell carcinoma is managed identically to other subtypes of lung squamous cell carcinoma. This article will help you understand the findings in your pathology report — what each term means and why it matters for your care.

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

Tobacco smoking is the most important cause of non-keratinizing squamous cell carcinoma of the lung, as it is for all subtypes of lung squamous cell carcinoma. The harmful chemicals in cigarette smoke damage the DNA inside the cells lining the airways, and over many years these changes accumulate and can cause a cell to become cancerous. The majority of people diagnosed with this cancer have a significant history of smoking.

Other risk factors include:

• Radon gas exposure — Radon is a naturally occurring radioactive gas that can build up inside homes and buildings. Long-term exposure is a recognized cause of lung cancer.
• Occupational exposures — Prolonged contact with substances such as asbestos, silica dust, nickel, chromium compounds, or arsenic in certain workplaces increases the risk of developing lung cancer.
• Air pollution — Long-term exposure to outdoor air pollution contributes modestly to lung cancer risk.
• Prior chest radiation — People who have received radiation therapy to the chest for a previous cancer have a small but recognized increased risk of developing a second lung cancer.

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

Like other subtypes of squamous cell carcinoma, non-keratinizing squamous cell carcinoma most often arises in the larger central airways of the lung. Its central location means it tends to cause airway-related symptoms, sometimes before the cancer has grown very large.

Common symptoms include:

• A persistent or worsening cough.
• Coughing up blood — more common in centrally located squamous cell carcinomas than in peripheral tumors.
• Shortness of breath or wheezing caused by partial blockage of an airway.
• Chest pain or discomfort.
• Recurrent pneumonia in the same area of the lung — a warning sign that an airway may be partially obstructed by a tumor, preventing normal mucus clearance.
• Fatigue and unexplained weight loss, particularly with more advanced disease.

If the cancer has spread to other parts of the body, additional symptoms may appear depending on which organs are involved. For example, spread to the bones can cause bone pain, and spread to the brain can cause headaches or neurological changes.

What conditions are associated with non-keratinizing squamous cell carcinoma of the lung?

Non-keratinizing squamous cell carcinoma is one of three recognized subtypes of squamous cell carcinoma of the lung, classified by how the cancer cells appear under the microscope.

• Keratinizing squamous cell carcinoma — The classic subtype, in which the tumor cells produce visible keratin — a structural protein — forming characteristic structures called keratin pearls under the microscope. This is the most readily identifiable subtype and is described as the most well-differentiated.
• Non-keratinizing squamous cell carcinoma — This diagnosis. The tumor cells have squamous features but do not produce visible keratin. Immunohistochemistry is required to confirm the squamous identity of these cells.
• Basaloid squamous cell carcinoma — A subtype in which the cancer cells resemble the basal (bottom layer) cells of the airway lining. This subtype is often associated with more aggressive behavior.

All three subtypes are classified as squamous cell carcinoma of the lung, are treated using the same approach, and carry a broadly similar prognosis when compared stage for stage. The subtype designation reflects microscopic appearance rather than a fundamentally different type of cancer.

How is the diagnosis made?

The diagnosis is usually first suspected when imaging — such as a chest X-ray or CT scan — reveals a suspicious mass or nodule, most often in the central part of the lung. A biopsy is then performed to obtain a small tissue sample for examination. Because non-keratinizing squamous cell carcinoma often arises near the central airways, it is frequently accessible by bronchoscopy — a procedure in which a thin flexible tube is passed through the mouth into the airways to collect a tissue sample directly. For tumors in less accessible locations, a CT-guided needle biopsy or fine needle aspiration (FNA) may be used instead.

Under the microscope, a pathologist identifies non-keratinizing squamous cell carcinoma by examining the tumor cells’ appearance. The cells are large, with irregular, variable shapes — a feature pathologists describe as pleomorphic. They grow in dense sheets or nests and have large, dark-staining nuclei with prominent nucleoli (the dark spots within a nucleus that direct protein production). Numerous mitotic figures — cells caught in the act of dividing — are typically present, reflecting how rapidly the cancer cells are multiplying. Crucially, no keratin pearls or intercellular bridges — the microscopic features that identify keratinizing squamous cell carcinoma — are visible. The cells appear bluer than pink under the microscope because they contain little keratin.

Because the non-keratinizing subtype lacks the characteristic features of squamous differentiation visible to the naked eye under the microscope, immunohistochemistry (IHC) is essential for confirming the diagnosis. IHC is a laboratory technique that uses antibodies linked to colored dyes to detect specific proteins inside the cells. Non-keratinizing squamous cell carcinoma characteristically shows strong positive staining for p40 and CK5 — proteins produced by squamous cells — and negative staining for TTF-1 (a marker of lung adenocarcinoma), chromogranin, and synaptophysin (markers of neuroendocrine tumors). This pattern of staining confirms the squamous cell identity of the tumor and rules out other types of lung cancer that can look similar under the microscope, particularly poorly differentiated adenocarcinoma and large cell neuroendocrine carcinoma.

Once the diagnosis is confirmed, imaging — typically CT of the chest and abdomen and often a PET scan — is used to determine how far the cancer has spread and to guide treatment planning.

Histologic grade

The histologic grade describes how closely the cancer cells resemble normal squamous cells under the microscope. In squamous cell carcinoma, grade is based primarily on the degree of keratinization and cellular organization, and because non-keratinizing squamous cell carcinoma shows no keratinization by definition, it falls into the intermediate or poorly differentiated category.

• Moderately differentiated (Grade 2) — The tumor cells show some squamous features, such as relatively organized cell arrangements, but produce no visible keratin. Many non-keratinizing squamous cell carcinomas are classified here.
• Poorly differentiated (Grade 3) — The tumor cells show minimal squamous features, with marked cellular irregularity and high mitotic activity. When no keratin production is present and the cells are highly irregular, Grade 3 is assigned. In practice, IHC is particularly important in these cases to confirm the squamous identity of the tumor.

Because keratinization is the main feature used to recognize well-differentiated (Grade 1) squamous cell carcinoma, Grade 1 is not assigned to the non-keratinizing subtype. The grade is one of several features that together give your care team a picture of how aggressively the tumor is likely to behave.

Spread through air spaces (STAS)

Spread through air spaces (STAS) means that cancer cells have been found floating within the small airways and air spaces of the lung beyond the edge of the main tumor. These cells have detached from the primary mass and traveled through the natural air channels of the lung.

• STAS not identified — No cancer cells are seen in the air spaces beyond the main tumor edge. This is the more favorable finding.
• STAS present — Cancer cells are identified in the surrounding air spaces. This finding is associated with a higher risk of recurrence after surgery, particularly after limited resections such as wedge resection, and may influence the type and extent of surgery recommended.

Multiple tumors

More than one tumor is occasionally found in the lung. Determining the relationship between multiple tumors is important because it affects staging, treatment, and prognosis.

When multiple tumors look identical under the microscope and share the same molecular profile, they are more likely to represent spread from a single primary cancer to another part of the lung. When the tumors differ in appearance or molecular profile — for example, one is non-keratinizing squamous cell carcinoma and another is adenocarcinoma — they are more likely to represent two independent primary cancers that arose separately. Molecular testing can help resolve ambiguous cases. Separate tumor nodules in the same lobe as the primary tumor increase the T stage to pT3; nodules in a different lobe of the same lung are classified as pT4.

Pleural invasion

The pleura is a thin membrane with two layers: the visceral pleura, which covers the outer surface of the lungs, and the parietal pleura, which lines the inside of the chest cavity. Pleural invasion means cancer cells have grown into one or both of these layers.

• Pleural invasion not identified — The tumor has not reached the pleural surface. This is the more favorable finding.
• Visceral pleural invasion — Cancer cells have grown through the elastic layer of the visceral pleura. This increases the T stage and is associated with a higher risk of recurrence.
• Parietal pleural invasion — Cancer cells have grown into the outer pleural layer lining the chest cavity, indicating more advanced local disease and further increasing the T stage.

Lymphovascular invasion

Lymphovascular invasion (LVI) means that cancer cells have been found within blood or lymphatic vessels — the small channels that carry lymph — in or near the tumor. These vessels can act as pathways for cancer cells to travel to lymph nodes or distant organs.

• Lymphovascular invasion not identified — No cancer cells are seen within vessels near the tumor. This is the more favorable finding.
• Lymphovascular invasion present — Cancer cells are found within vessels. This is associated with a higher risk of lymph node involvement and distant metastasis and may influence decisions about additional treatment after surgery.

Surgical margins

Surgical margins are the cut edges of the tissue removed during an operation. The pathologist examines all margins to determine whether the tumor was completely removed. In lung cancer surgery, the margins typically assessed include the bronchial margin (where the airway was divided), the vascular margins (where blood vessels were cut), and the parenchymal margin (the edge of the surrounding lung tissue).

• Negative margin — No cancer cells are seen at the cut edge of the tissue. This indicates the tumor was fully removed and is the most favorable outcome.
• Close margin — Cancer cells are present very near the cut edge but do not reach it. Further treatment may be recommended depending on the distance and the specific margin involved.
• Positive margin — Cancer cells are present at the cut edge. This raises concern that some tumor remains and typically leads to discussion of further surgery or radiation therapy to the area.

Lymph nodes

Lymph nodes are small immune organs distributed throughout the chest. During surgery, the surgeon removes lymph nodes from specific locations within the lung and central chest — called lymph node stations — and sends them to the pathologist for examination under the microscope.

The pathology report will describe the total number of lymph nodes examined, their station locations, whether any contain cancer cells, and the size of any deposits found. The number and location of involved lymph nodes determine the nodal stage (N stage) and are one of the most important factors in deciding whether additional treatment, such as chemotherapy or radiation, is recommended. In some cases, cancer cells may have broken through the outer wall of a lymph node and spread into the surrounding tissue — a finding called extranodal extension — which indicates more aggressive disease.

Biomarker and molecular testing

Biomarkers are measurable changes in the DNA or proteins of cancer cells that provide important information about how the tumor will behave and which treatments are most likely to work. Biomarker testing is a standard part of the workup for non-keratinizing squamous cell carcinoma of the lung, particularly in patients with advanced or metastatic disease. The biomarker landscape for all subtypes of lung squamous cell carcinoma is the same — the non-keratinizing subtype does not change which tests are performed or which treatments are available. The most clinically important biomarkers relate to immunotherapy eligibility, because squamous cell carcinoma less frequently harbors the targetable driver mutations — such as EGFR or ALK — that are common in adenocarcinoma.

PD-L1

PD-L1 (programmed death-ligand 1) is a protein that some cancer cells display on their surface to hide from the immune system. Drugs called checkpoint inhibitors block this mechanism, restoring the immune system’s ability to recognize and attack the cancer. PD-L1 is measured by immunohistochemistry and reported as the Tumor Proportion Score (TPS) — the percentage of tumor cells showing surface PD-L1 staining. PD-L1 testing is performed on all newly diagnosed advanced squamous cell carcinomas and is the primary biomarker guiding first-line immunotherapy decisions.

• TPS <1% — PD-L1 negative. Chemotherapy combined with immunotherapy is generally preferred over immunotherapy alone.
• TPS 1–49% — Low to intermediate PD-L1 expression. Pembrolizumab combined with chemotherapy is a standard first-line option.
• TPS ≥50% — High PD-L1 expression. Pembrolizumab (Keytruda) alone — without chemotherapy — is a standard first-line option, with response rates of approximately 45–50% in patients with TPS ≥50%.

Tumor mutational burden (TMB)

Tumor mutational burden (TMB) measures the number of mutations in a cancer cell’s DNA. Tumors with a high mutation count (TMB ≥10 mutations per megabase of DNA) tend to be more visible to the immune system and more likely to respond to checkpoint immunotherapy. Squamous cell carcinoma, with its strong association with tobacco smoking, often carries a high TMB. Pembrolizumab is approved for any solid tumor with TMB ≥10 mut/Mb that has progressed after prior treatment. TMB is measured by next-generation sequencing (NGS) and reported as a numerical value in mut/Mb.

Mismatch repair (MMR) and microsatellite instability (MSI)

Mismatch repair (MMR) is a system of proteins that corrects errors in DNA copying. When this system fails, the cancer is described as mismatch repair deficient (dMMR), and a related condition called microsatellite instability-high (MSI-H) develops. MMR deficiency is uncommon in lung squamous cell carcinoma (approximately 1–2%) but is important because dMMR and MSI-H tumors respond well to checkpoint immunotherapy. Pembrolizumab is approved for any solid tumor that is dMMR or MSI-H regardless of cancer type. Testing is performed by immunohistochemistry for the four MMR proteins (MLH1, PMS2, MSH2, MSH6). Your report will describe the result as MMR intact (pMMR) or MMR deficient (dMMR).

Driver mutation and broad molecular profiling

Targetable driver mutations such as EGFR mutations and ALK rearrangements are uncommon in squamous cell carcinoma of the lung, including the non-keratinizing subtype. Despite this, current guidelines recommend performing broad molecular profiling by next-generation sequencing (NGS) on all patients with advanced NSCLC, including squamous cell carcinoma. This is done for two reasons: rare but actionable alterations do occasionally occur, particularly in never-smokers; and comprehensive profiling may identify eligibility for clinical trials targeting alterations such as FGFR1 amplification or FGFR2/3 rearrangements, which are found in approximately 10–20% of lung squamous cell carcinomas and are being studied as potential targets. Your report or a separate molecular testing report will describe the results of any NGS panel performed.

For more information about biomarker testing in cancer, visit the Biomarkers and Molecular Testing section of MyPathologyReport.

Pathologic stage (pTNM)

Non-keratinizing squamous cell carcinoma of the lung is staged using the TNM system based on AJCC 8th edition criteria. The T category describes the size of the tumor and whether it has grown into nearby structures. The N category indicates whether cancer has spread to nearby lymph nodes. The M category — which describes spread to distant organs such as the brain, bones, or liver — is determined by imaging rather than the pathology specimen and is typically not reported in the surgical pathology report. Together, T, N, and M are combined to determine an overall stage, ranging from I (earliest) to IV (most advanced).

Tumor stage (pT)

• pT1a — Tumor is 1 cm or smaller, surrounded by lung or visceral pleura, with no involvement of the main bronchus.
• pT1b — Tumor is larger than 1 cm but no larger than 2 cm, otherwise meeting T1a criteria.
• pT1c — Tumor is larger than 2 cm but no larger than 3 cm, otherwise meeting T1a criteria.
• pT2a — Tumor is larger than 3 cm but no larger than 4 cm; or the tumor — regardless of size — has grown into the visceral pleura, involves the main bronchus without reaching the carina, or is associated with partial lung collapse.
• pT2b — Tumor is larger than 4 cm but no larger than 5 cm, otherwise meeting T2a criteria.
• pT3 — Tumor is larger than 5 cm but no larger than 7 cm; or the tumor has grown into the chest wall, phrenic nerve, or parietal pericardium; or a separate tumor nodule is present in the same lobe as the primary tumor.
• pT4 — Tumor is larger than 7 cm; or the tumor has grown into major structures such as the heart, large blood vessels, trachea, esophagus, or spine; or a separate tumor nodule is present in a different lobe of the same lung.

Nodal stage (pN)

• pNX — Lymph nodes were not examined.
• pN0 — No cancer cells found in any lymph nodes examined.
• pN1 — Cancer cells found in lymph nodes within the lung or near the main airway on the same side of the chest (intrapulmonary, hilar, or peribronchial nodes; stations 10–14).
• pN2 — Cancer cells found in lymph nodes in the central chest on the same side (ipsilateral mediastinal or subcarinal nodes; stations 4–9).
• pN3 — Cancer cells found in lymph nodes on the opposite side of the chest or in the lower neck (contralateral mediastinal, contralateral hilar, scalene, or supraclavicular nodes). This indicates advanced nodal disease.

Treatment effect

If you received chemotherapy or radiation therapy before surgery — a strategy called neoadjuvant treatment — your pathology report will describe the treatment effect: an assessment of how much of the original tumor was destroyed by that pre-surgical treatment. The pathologist estimates the proportion of the tumor that still contains living (viable) cancer cells after treatment and expresses this as a percentage. A lower percentage of viable tumor indicates a better response. This information helps your oncology team assess how well the pre-surgical treatment worked and guides decisions about any additional therapy after surgery.

What is the prognosis?

The prognosis for non-keratinizing squamous cell carcinoma is broadly similar to that of other subtypes of lung squamous cell carcinoma when compared stage for stage. The subtype designation reflects how the tumor cells appear under the microscope, not a fundamentally different clinical behavior. Outcomes depend primarily on the stage at diagnosis, the histologic grade, the presence of specific pathologic features, and the response to treatment.

• Stage I — Five-year survival after complete surgical resection is approximately 70–85% for stage IA and 55–65% for stage IB.
• Stage II — Five-year survival is approximately 45–55%. Adjuvant chemotherapy is recommended after surgery for most patients with stage II disease.
• Stage III — Five-year survival ranges from approximately 15–35% depending on the extent of nodal involvement. Concurrent chemoradiation followed by durvalumab immunotherapy consolidation is standard for unresectable stage III disease.
• Stage IV — Outcomes have improved with modern immunotherapy. Patients with high PD-L1 expression (TPS ≥50%) treated with pembrolizumab monotherapy have median overall survivals of approximately 20–26 months in clinical trials.

Pathologic features associated with a higher risk of recurrence include poorly differentiated histologic grade, lymphovascular invasion, pleural invasion, positive or close surgical margins, STAS, and lymph node involvement.

What happens after the diagnosis?

After the pathology report is finalized, your doctor will review the findings along with your imaging results, molecular profile, and overall health to develop a treatment plan. Non-keratinizing squamous cell carcinoma is managed as an NSCLC subtype by a multidisciplinary team comprising a thoracic surgeon, medical oncologist, radiation oncologist, respirologist, and pathologist.

For early-stage disease (stages I and II), surgery to remove the tumor is the primary treatment. Options include wedge resection (removal of a small wedge of lung tissue), segmentectomy (removal of a defined anatomical lung segment), lobectomy (removal of an entire lobe), or — rarely — pneumonectomy (removal of the entire lung). Lobectomy is the standard approach for most tumors when the patient’s lung function permits. After surgery, adjuvant chemotherapy is recommended for most patients with stage II disease. Unlike adenocarcinoma, there is currently no approved adjuvant targeted therapy for squamous cell carcinoma, though immunotherapy trials in the adjuvant setting are an active area of research.

For locally advanced disease (stage III), treatment typically combines chemotherapy and radiation. Durvalumab (Imfinzi) given after definitive chemoradiation has been shown to significantly improve survival and is now a standard approach for unresectable stage III NSCLC.

For advanced or metastatic disease (stage IV), treatment is guided primarily by PD-L1 expression and TMB, as targetable driver mutations are uncommon in squamous cell carcinoma. Options include pembrolizumab alone (for TPS ≥50%), pembrolizumab combined with chemotherapy, or other checkpoint inhibitor-based regimens. Molecular profiling by NGS is performed to identify any rare actionable alterations or clinical trial opportunities.

Follow-up after treatment includes regular chest CT imaging and physical examinations to monitor for recurrence. The frequency and duration of follow-up will be guided by your care team based on your stage and treatment received.

Questions to ask your doctor

• Why was my tumor classified as non-keratinizing squamous cell carcinoma rather than another subtype, and does this affect my treatment?
• What is the histologic grade of my tumor, and what does it mean for my prognosis?
• What stage is my cancer, and what does that mean for my treatment options?
• Was STAS (spread through air spaces) identified in my pathology report?
• Was pleural invasion or lymphovascular invasion found?
• Were the surgical margins clear? If not, what are the next steps?
• Did the cancer spread to any lymph nodes, and if so, how many and in which locations?
• What was my PD-L1 score, and does it affect my eligibility for immunotherapy?
• Was broad molecular profiling (NGS) performed on my tumor, and what were the results?
• Was my tumor found to be MMR-deficient or MSI-high?
• Is adjuvant treatment recommended after surgery?
• If I received treatment before surgery, what did the treatment effect assessment show?
• Are there clinical trials I might be eligible for?
• What is my follow-up schedule, and what symptoms should prompt me to contact you sooner?