Large Cell Neuroendocrine Carcinoma of the Lung: Understanding Your Pathology Report

By Jason Wasserman MD PhD FRCPC
April 29, 2026

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Large cell neuroendocrine carcinoma (LCNEC) is an aggressive, high-grade lung cancer that develops from neuroendocrine cells — specialized cells found in small numbers throughout the walls of the airways that normally produce hormones and chemical signals. LCNEC is classified as a Grade 3 neuroendocrine carcinoma — the highest grade in the lung neuroendocrine tumor family, shared with small cell carcinoma. It grows quickly, spreads early, and generally requires prompt treatment. Despite its aggressive behavior, LCNEC has unique molecular features that distinguish it from small cell carcinoma and directly influence which treatments are most likely to be effective. 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 large cell neuroendocrine carcinoma of the lung?

Tobacco smoking is the most common cause of LCNEC and is present in the history of the large majority of affected patients. The link between smoking and LCNEC is strong — comparable to that seen with squamous cell carcinoma and small cell carcinoma — because the chemicals in cigarette smoke damage the DNA of airway cells over many years, accumulating mutations that eventually cause a cell to become cancerous.

Other risk factors include:

• Radon gas exposure — Radon is a naturally occurring radioactive gas that can accumulate in homes and buildings. Long-term radon 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.
• Prior chest radiation — People who have received radiation therapy to the chest for a previous cancer have a modestly increased risk of developing a second lung cancer.

LCNEC can occasionally occur in people who have never smoked, in which case the underlying cause is often unclear.

What are the symptoms of large cell neuroendocrine carcinoma of the lung?

Symptoms depend on the size and location of the tumor. LCNEC arises in both central and peripheral locations within the lung, and its symptoms reflect where it grows.

Tumors within or near the central airways may cause:

• A persistent or worsening cough.
• Coughing up blood.
• Shortness of breath or wheezing.
• Recurrent pneumonia in the same part of the lung, caused by partial airway obstruction.
• Chest pain or pressure.

Peripheral tumors are often silent in their early stages and may be detected incidentally on imaging. As the cancer grows and spreads, additional symptoms may appear:

• Unexplained weight loss and fatigue.
• Bone pain occurs if the cancer has spread to the bone.
• Abdominal pain or a sense of fullness, if the cancer has spread to the liver or adrenal glands.
• Headache, confusion, or other neurological symptoms, if the cancer has spread to the brain.

Because LCNEC is composed of neuroendocrine cells, it can occasionally produce hormones — for example, ACTH (which can cause Cushing syndrome) or antidiuretic hormone (which can cause abnormally low blood sodium). These paraneoplastic effects are less common than in small cell carcinoma but can occur and should be mentioned to your care team if you experience unexplained hormonal symptoms.

What conditions are associated with large cell neuroendocrine carcinoma of the lung?

LCNEC belongs to the family of lung neuroendocrine tumors, which are classified by their grade — a measure of how aggressively they grow and how likely they are to spread. Understanding where LCNEC sits in this spectrum explains its relationship to the carcinoid tumors and to small cell carcinoma, which patients may encounter when seeking information about their diagnosis.

• Typical carcinoid tumor (Grade 1) — The least aggressive lung neuroendocrine tumor. Defined by fewer than 2 cell divisions per 2 square millimeters and no necrosis. Cured by surgery in the great majority of cases. Learn more about typical carcinoid tumor of the lung.
• Atypical carcinoid tumor (Grade 2) — An intermediate-grade neuroendocrine tumor with 2–10 cell divisions per 2 square millimeters or the presence of necrosis. More prone to spread than typical carcinoid but still significantly less aggressive than LCNEC. Learn more about atypical carcinoid tumor of the lung.
• Large cell neuroendocrine carcinoma (Grade 3) — This diagnosis. A high-grade neuroendocrine carcinoma with more than 10 cell divisions per 2 square millimeters and prominent areas of necrosis. Grows and spreads rapidly, requiring prompt systemic treatment.
• Small cell carcinoma (Grade 3) — The other high-grade neuroendocrine carcinoma of the lung. Shares Grade 3 classification with LCNEC but has a distinct microscopic appearance — smaller cells with less cytoplasm and different nuclear features — and is managed somewhat differently. Learn more about small cell carcinoma of the lung.

LCNEC is also sometimes compared to large cell carcinoma, a non-neuroendocrine lung cancer made up of large, undifferentiated cells. Despite the similar name, large cell carcinoma and LCNEC are fundamentally different tumors: LCNEC shows neuroendocrine features under the microscope and on special protein tests, while large cell carcinoma does not. The distinction matters because treatment approaches differ. It is also worth noting that on a small biopsy sample, the full picture of LCNEC may not be apparent, and the diagnosis may be refined — sometimes from “large cell carcinoma” to LCNEC — after the entire tumor is examined surgically.

How is the diagnosis made?

LCNEC is usually diagnosed from a tissue sample obtained by biopsy. Because LCNEC can arise in both central and peripheral lung locations, the biopsy may be obtained via bronchoscopy (a flexible tube passed into the airways), CT-guided needle biopsy through the chest wall, endobronchial ultrasound (EBUS), or fine-needle aspiration (FNA). In some cases, the diagnosis is made or confirmed on the surgically removed tumor. On small biopsy samples, pathologists can identify high-grade neuroendocrine features but may not be able to make a definitive distinction between LCNEC and other high-grade carcinomas — in which case the diagnosis may be revised after the full surgical specimen is examined.

Under the microscope, a pathologist identifies LCNEC by a combination of features. The tumor cells are large — significantly larger than those of small cell carcinoma — with a moderate amount of pale pink cytoplasm. The cell nucleus contains coarsely clumped or vesicular chromatin, and prominent nucleoli are typically visible — features that distinguish LCNEC from small cell carcinoma, in which nucleoli are characteristically absent. The cells grow in organized architectural patterns — described by pathologists as organoid nests, trabecular cords, palisading (cells lining up along one edge of a cluster), and rosettes (cells arranged in a ring around a central space) — reflecting their neuroendocrine origin. The pathologist counts the number of mitotic figures (cells in the process of dividing) in a standardized area of 2 square millimeters: LCNEC requires more than 10 mitotic figures per 2 square millimeters. Areas of necrosis — patches of dead tumor cells — are also typically present, often appearing as geographic zones of cell death within the tumor nests.

To confirm the neuroendocrine identity of the tumor cells, the pathologist performs immunohistochemistry (IHC) — a laboratory technique that uses antibodies linked to colored dyes to detect specific proteins within the cells. LCNEC characteristically shows positive staining for one or more neuroendocrine markers, including synaptophysin, chromogranin, and CD56. TTF-1, a lung lineage marker, may also be positive. Importantly, a subset of LCNEC tumors may show weak or even absent staining for neuroendocrine markers on IHC — in these cases, the diagnosis is supported by the characteristic microscopic architecture described above. The Ki-67 proliferation index — a measure of the fraction of cells actively dividing — is typically very high in LCNEC, generally greater than 50% and often exceeding 70%, reflecting the rapid growth rate of these tumors and distinguishing them from the lower-grade carcinoid tumors (Ki-67 below 20%).

Once the diagnosis is confirmed, imaging — including chest and abdominal CT, brain MRI, and often a PET scan — is performed to assess the full extent of disease throughout the body. Molecular profiling by next-generation sequencing (NGS) is increasingly performed at diagnosis to identify the molecular subtype of the tumor and guide treatment planning (see Biomarker and molecular testing section below).

Histologic grade

Large cell neuroendocrine carcinoma of the lung is classified as Grade 3 (high-grade neuroendocrine carcinoma) in the 2021 WHO Classification of Thoracic Tumors. Grade 3 is the highest grade in the lung neuroendocrine tumor classification system and is shared between LCNEC and small cell carcinoma. The Grade 3 designation reflects the defining features of the diagnosis: a mitotic count greater than 10 per 2 square millimeters and the presence of necrosis, the same features used to make the diagnosis.

Because the grade is embedded in the diagnostic criteria, all LCNEC tumors are by definition Grade 3. This places LCNEC in a very different clinical category from the carcinoid tumors: Grade 3 tumors grow rapidly, spread early, and require immediate and aggressive treatment. However, within Grade 3, LCNEC and small cell carcinoma are biologically distinct — a distinction that has become increasingly important as molecular profiling has revealed that the two tumor types differ in their genetic alterations and in their responses to different chemotherapy regimens.

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 separated 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. This is the more favorable finding.
• STAS present — Cancer cells are identified in the air spaces surrounding the tumor. This finding is associated with a higher risk of recurrence after surgery, particularly after limited resections such as wedge resection, and may influence the surgical team’s decision about the type and extent of resection.

Multiple tumors

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

When multiple tumors look identical under the microscope and carry the same molecular profile, they are more likely to represent spread from a single primary tumor to another part of the lung. When the tumors differ in appearance or molecular alterations — for example, one is LCNEC, and another is adenocarcinoma — they are more likely to represent two independent primary cancers that arose separately. Molecular profiling can help resolve ambiguous cases. Separate tumor nodules in the same lobe as the primary tumor increase the T stage to pT3; separate 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 and spread.
• 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 serve as pathways for cancer cells to travel to distant parts of the body.

• 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 identified within vessels. This finding 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.

• Negative margin — No cancer cells are seen at the cut edge of the tissue. This indicates that the tumor was fully removed, which 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 location.
• 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. Lymph node involvement is common in LCNEC at diagnosis, reflecting its aggressive biology and tendency for early spread. The location of involved nodes — within the lung (N1), in the central chest on the same side (N2), or on the opposite side or in the neck (N3) — strongly influences the overall stage, treatment decisions, and prognosis. In some cases, cancer cells may have broken through the outer wall of a lymph node and spread into surrounding tissue — a finding called extranodal extension, which indicates more aggressive disease.

Biomarker and molecular testing

Biomarker and molecular testing plays an increasingly important role in the management of LCNEC — more so than for any other lung neuroendocrine tumor. This is because molecular profiling has revealed that LCNEC is not a single biologically uniform disease: it comprises two distinct molecular subtypes with different genetic profiles and, critically, different sensitivities to chemotherapy. Understanding which subtype a patient has is becoming a standard part of treatment planning at specialized centers.

Molecular subtypes: SCLC-like versus NSCLC-like LCNEC

Next-generation sequencing (NGS) — a comprehensive test that reads many genes simultaneously — has shown that LCNEC tumors fall into two major groups based on their mutational profiles.

The first group, called SCLC-like LCNEC, harbors mutations that are typical of small cell carcinoma — most importantly, loss of the RB1 gene (a key tumor suppressor that normally limits cell division) combined with mutations in TP53. These tumors tend to respond better to the chemotherapy regimen used in small cell carcinoma: carboplatin or cisplatin combined with etoposide.

The second group, called NSCLC-like LCNEC, harbors mutations more typical of non-small cell lung cancer — including STK11, KEAP1, and KRAS mutations — with an intact RB1 gene. These tumors tend to respond better to NSCLC-type chemotherapy regimens such as carboplatin combined with paclitaxel or pemetrexed.

This distinction is clinically meaningful: patients whose LCNEC are treated with chemotherapy matched to their molecular subtype tend to have better outcomes. Molecular profiling by NGS is therefore increasingly recommended at the time of diagnosis for patients with LCNEC. Your report or a separate molecular testing report will describe the results of any NGS panel performed.

PD-L1

PD-L1 (programmed death-ligand 1) is a protein that some cancer cells display on their surface to evade immune attack. Drugs called checkpoint inhibitors block this mechanism, restoring the immune system’s ability to recognize and attack the cancer. PD-L1 expression is assessed by immunohistochemistry and reported as the Tumor Proportion Score (TPS) — the percentage of tumor cells showing surface PD-L1 staining. In LCNEC, PD-L1 is expressed in a subset of cases. The clinical significance of PD-L1 testing in LCNEC is less well established than in non-small cell lung cancer, but checkpoint immunotherapy is used in clinical practice for advanced LCNEC — particularly in NSCLC-like tumors — and PD-L1 expression may support its use. Your care team will interpret the PD-L1 result in the context of your overall molecular profile and treatment plan.

Tumor mutational burden (TMB)

Tumor mutational burden (TMB) is a measure of the number of mutations in a cancer cell’s DNA. LCNEC, given its strong association with tobacco smoking, frequently carries a high mutational burden. Pembrolizumab is FDA-approved for any solid tumor with TMB ≥10 mutations per megabase of DNA that has progressed after prior treatment, and this approval may apply to LCNEC. TMB is measured by NGS and reported as mutations per megabase (mut/Mb). Your report will state the numerical TMB value and whether it meets the ≥10 mut/Mb threshold.

EGFR, ALK, and other driver mutations

Targetable driver mutations, such as EGFR mutations, ALK rearrangements, and ROS1 rearrangements, are found in a small minority of LCNEC tumors — particularly in the NSCLC-like subgroup and among never-smokers. While their frequency in LCNEC is much lower than in lung adenocarcinoma, identifying them is important because targeted therapy may be an effective treatment option when present. Comprehensive NGS panels simultaneously test for these and many other actionable alterations. Your report or molecular profile will describe the findings.

Mismatch repair (MMR) and microsatellite instability (MSI)

Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) are uncommon in LCNEC but can occur. When present, these tumors are eligible for pembrolizumab under its tumor-agnostic approval. 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).

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

Pathologic stage (pTNM)

LCNEC 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 liver, bone, or brain — 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.

What is the prognosis?

The prognosis for LCNEC is significantly worse than for the carcinoid tumors and is broadly comparable to that of small cell carcinoma, though outcomes vary by stage and molecular subtype. LCNEC tends to present at an advanced stage in many patients, reflecting its rapid growth and early spread.

• Stage I — Five-year survival after complete surgical resection is approximately 40–60%, which is substantially lower than for non-small cell lung cancers at the same stage. Even after complete resection, the risk of distant recurrence is high, which is why adjuvant chemotherapy is generally recommended.
• Stage II–III — Five-year survival falls to approximately 15–35% with combined surgery and adjuvant chemotherapy for operable patients. Unresectable stage III disease is treated with combined chemotherapy and radiation.
• Stage IV — Median survival with systemic treatment is approximately 8–15 months. Outcomes may be improved in patients with the NSCLC-like molecular subtype treated with matched chemotherapy, and in those with targetable driver mutations or high PD-L1 expression who respond to targeted therapy or immunotherapy.

Pathologic features associated with a higher risk of recurrence and worse outcomes include:

• Lymph node involvement — The most important predictor of recurrence in resected LCNEC.
• Positive or close surgical margins.
• Lymphovascular invasion.
• Pleural invasion.
• STAS (spread through air spaces).

What happens after the diagnosis?

After the pathology report is finalized, your doctor will review the findings together with your imaging results, molecular profile, and overall health to develop a treatment plan. LCNEC is managed by a multidisciplinary team including a thoracic surgeon, medical oncologist, radiation oncologist, respirologist, and pathologist.

For early-stage disease (stages I–II) in patients fit for surgery, surgical resection — typically lobectomy with systematic lymph node dissection — is the primary treatment. Because of the high risk of distant recurrence even after complete resection, adjuvant chemotherapy is generally recommended. The choice of regimen — SCLC-type (carboplatin/cisplatin + etoposide) versus NSCLC-type (carboplatin + paclitaxel or pemetrexed) — is increasingly guided by the molecular subtype identified on NGS. If the molecular profile is unavailable, current guidelines generally favor the SCLC-type regimen for purely neuroendocrine tumors and the NSCLC-type regimen for tumors with combined NSCLC features.

For locally advanced disease (stage III), treatment depends on whether the tumor is surgically resectable. Resectable stage III tumors are managed with surgery followed by adjuvant chemotherapy. Unresectable stage III tumors are treated with concurrent chemotherapy and radiation. Durvalumab immunotherapy consolidation after chemoradiation, while established for non-small cell lung cancer at this stage, has less established evidence in LCNEC specifically, but may be considered by the treating team.

For advanced or metastatic disease (stage IV), treatment is systemic. Options include:

• Chemotherapy matched to molecular subtype — Platinum-etoposide for SCLC-like tumors; platinum-paclitaxel or platinum-pemetrexed for NSCLC-like tumors.
• Checkpoint immunotherapy — Pembrolizumab or other checkpoint inhibitors for patients with high PD-L1 expression, high TMB, or dMMR/MSI-H tumors.
• Targeted therapy — When a targetable driver mutation (such as an EGFR mutation or ALK rearrangement) is identified, the appropriate targeted drug may be used.
• Clinical trials — Given the rarity of LCNEC and the active evolution of its treatment landscape, clinical trials are an important option, and your oncology team can advise whether any are appropriate.

Follow-up after treatment includes regular chest and abdominal CT imaging, brain MRI (given the risk of brain metastasis), and physical examinations. The frequency and duration of follow-up will be determined by your care team based on your stage and treatment.

Questions to ask your doctor

• Has molecular profiling (NGS) been performed on my tumor, and what molecular subtype is it — SCLC-like or NSCLC-like?
• What treatment regimen is recommended based on my molecular subtype?
• What is my pathologic stage, and what does it mean for my prognosis?
• Was the tumor completely removed, and what were the surgical margins?
• Did the cancer spread to any lymph nodes, and how many were examined?
• Was lymphovascular invasion or STAS identified in my pathology report?
• Was pleural invasion present, and how does it affect my stage?
• What was my PD-L1 score, and does it affect my eligibility for immunotherapy?
• Was my tumor found to be MMR-deficient or MSI-high?
• Is adjuvant chemotherapy recommended after surgery, and which regimen?
• Were any targetable driver mutations, such as EGFR or ALK, identified?
• 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?