Large cell neuroendocrine carcinoma of the lung

By Jason Wasserman MD PhD FRCPC
December 29, 2022

What is large cell neuroendocrine carcinoma of the lung?

Large cell neuroendocrine carcinoma (LCNEC) is an aggressive type of lung cancer made up of neuroendocrine cells. Neuroendocrine cells are specialized cells that are found throughout the body. They produce chemicals called hormones that influence the activity of both nearby and distant tissues.

Can large cell neuroendocrine carcinoma of the lung spread to other parts of the body?

Yes. LCNEC is an aggressive type of cancer that often metastasizes (spreads) to other areas of the body. Common sites for metastasis include the liver, adrenal glands, bones, and brain.

Where in the lung does large cell neuroendocrine carcinoma start?

LCNEC starts from specialized neuroendocrine cells that are normally found in the walls of the airways throughout the lungs. As the tumour gets bigger, the cells invade (spread) into the lung tissue around the airway.

What causes large cell neuroendocrine carcinoma in the lung?

The most common cause of LCNEC is cigarette smoking. People who are exposed to second-hand cigarette smoke for many years are also at risk for developing LCNEC.

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

Common symptoms of LCNEC include shortness of breath, worsening cough, coughing up blood, and chest pain or pressure. Symptoms related to metastatic disease (tumour cells that have spread from the lung to other parts of the body) include weight loss, abdominal pain, bone pain, and new or worsening headaches.

How is this diagnosis made?

The diagnosis of LCNEC is usually made after a small sample of tissue is removed from the tumour and examined under the microscope by a pathologist. Procedures performed to remove the tissue sample include fine needle aspiration biopsy (FNAB) and core needle biopsy.

What does large cell neuroendocrine carcinoma look like under the microscope?

When examined under the microscope, LCNEC is made up of large abnormal-looking cells arranged in groups. Pathologists use terms such as organoid, nested, trabecular, palisading, and rosettes, to describe the groups and multiple patterns can be seen in the same tumour. The tumour cells often have a moderate amount of eosinophilic (pink) cytoplasm (the material inside the body of the cell) and large clumps of genetic material can be seen in a part of the cell called the nucleus. Pathologists use the terms coarse or vesicular to describe this kind of clumpy genetic material. The term nucleolus (pleural nucleoli) is used to describe a single large clump is genetic material. It is very common for the tumour cells in LCNEC to have one or more prominent nucleoli.

In order to make the diagnosis of LCNEC your pathologist must see mitotic figures (tumour cells dividing to create new tumour cells) and the number of mitotic figures must be greater than 10 in an area measuring 2 mm². A type of cell death called necrosis is also commonly seen but is not required to make the diagnosis.

What other tests may be ordered to confirm the diagnosis?

After examining the initial hematoxylin and eosin (H&E)-stained slides, your pathologist may order a test called immunohistochemistry to confirm the diagnosis. This test allows pathologists to ‘see’ the types of proteins being made by the tumour cells and can help distinguish LCNEC from other tumours that can look like LCNEC.

LCNEC starts from specialized neuroendocrine cells and the tumour cells usually continue to make proteins normally found in these cells. For this reason, LCNEC is often positive for at least one of the following markers: CD56, synaptophysin, or chromogranin. LCNEC is often also positive for TTF-1 but this marker is also found in other types of lung cancer such as adenocarcinoma.

What does pleural invasion mean and why is it important?

​The lungs are surrounded by a thin layer of tissue called the pleura. The pleura has both an inner and outer lining. The inner lining is called the visceral pleura and it touches the lung. The outer lining is called the parietal pleural and it is separated from the visceral pleural by a space called the pleural cavity.

Tumours that break through the visceral pleura can spread into the pleural space and from there to other parts of the body. For this reason, your pathologist will closely examine all the sections of the pleura under the microscope to see if any tumour cells have passed the visceral pleural. The movement of tumour cells through the visceral pleural is called pleural invasion. Pleural invasion increases the pathologic tumour stage (pT) and is associated with a worse prognosis.

Has the tumour spread outside of the lung?

The lung is surrounded by several organs including bones, muscles, the diaphragm, the heart, the esophagus, and the trachea. Large tumours can grow beyond the lung and into any of these surrounding organs. Invasion into another organ increases the pathologic tumour stage (pT) and is associated with a worse prognosis.

Other important information that may be found in your pathology report for large cell neuroendocrine carcinoma of the lung:

Lymphovascular invasion

Lymphovascular invasion means that tumour cells were seen inside of a blood vessel or lymphatic vessel. Blood vessels are long thin tubes that carry blood around the body. Lymphatic vessels are similar to small blood vessels except that they carry a fluid called lymph instead of blood. The lymphatic vessels connect with small immune organs called lymph nodes that are found throughout the body. Lymphovascular invasion is important because tumour cells can use blood vessels or lymphatic vessels to spread to other parts of the body such as lymph nodes or the liver.

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.

Most pathology reports only describe margins after a surgical procedure called an excision or resection has been performed for the purpose of removing the entire tumour. For this reason, margins are not usually described after a procedure called a biopsy is performed for the purpose of removing only part of the tumour. The number of margins described in a pathology report depends on the types of tissues removed and the location of the tumour. The size of the margin (the amount of normal tissue between the tumour and the cut edge) depends on the type of tumour being removed and the location of the tumour.

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. Tumour 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 tumour cells. The movement of tumour 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 tumour cells. If tumour cells were seen in a lymph node, the size of the largest group of tumour 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 tumour cells in a lymph node increases the risk that tumour 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.

What is the pathologic stage (pTNM) for large cell neuroendocrine carcinoma of the lung?

​The pathologic stage for LCNEC is based on the TNM staging system, an internationally recognized system originally 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) for large cell neuroendocrine carcinoma

LCNEC of the lung is given a tumour stage between 1 and 4 based on the size of the tumour, the number of tumours found in the tissue examined, and whether there is pleural invasion or the tumour has spread to organs around the lungs.

Nodal stage (pN) for large cell neuroendocrine carcinoma

LCNEC of the lung is given a nodal stage between 0 and 3 based on the presence or absence of tumour 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.

Metastatic stage (pM) for large cell neuroendocrine carcinoma

LCNEC of the lung is given a metastatic stage of 0 or 1 based on the presence of tumour cells in the lung on the opposite side of the body or at a distant body site (for example the brain). The metastatic stage can only be determined if tissue from the opposite lung or distant site is sent for pathological examination. Because this tissue is rarely present, the metastatic stage cannot be determined and is listed as pMX.