Poorly differentiated neuroendocrine carcinoma of the stomach

By Jason Wasserman MD PhD FRCPC
July 27, 2025

Poorly differentiated neuroendocrine carcinoma (NEC) is a rare and aggressive type of stomach cancer. It develops from specialized neuroendocrine cells found in the lining of the stomach. These cells normally help regulate digestive functions by releasing small hormone-like molecules. In NEC, these cells become cancerous and divide quickly, often forming a large tumor that can spread rapidly to other parts of the body.

There are two main types of poorly differentiated NEC of the stomach: small cell carcinoma and large cell carcinoma. Both types are considered high-grade tumors and are grouped together under the term “poorly differentiated neuroendocrine carcinoma.”

What are the symptoms of poorly differentiated neuroendocrine carcinoma of the stomach?

Symptoms of poorly differentiated NEC may include:

  • Abdominal pain or discomfort.

  • Unexplained weight loss.

  • Nausea or vomiting.

  • Fatigue.

  • A feeling of fullness after eating small amounts.

  • Bleeding in the stomach, which may cause black stools or vomiting blood.

Because these symptoms are common in many digestive conditions, poorly differentiated NEC is often diagnosed at an advanced stage.

What causes poorly differentiated neuroendocrine carcinoma?

The exact cause of poorly differentiated NEC is not fully understood, but several factors may increase the risk:

Unlike some other types of stomach cancer, poorly differentiated NEC is not typically linked to Helicobacter pylori infection or autoimmune gastritis.

How is this diagnosis made?

The diagnosis of poorly differentiated NEC is usually made after a biopsy, where a small piece of tissue is removed from the stomach during an endoscopy and examined under a microscope by a pathologist. Larger specimens removed during surgery are also examined to confirm the diagnosis and determine how far the cancer has spread.

What does poorly differentiated NEC look like under the microscope?

When viewed under the microscope, poorly differentiated NEC is made up of abnormal-looking cells that are larger and more irregular than normal neuroendocrine cells. These cancer cells divide rapidly and often form solid sheets or clusters. A special feature of these tumors is their high mitotic rate, which means many of the cells are actively dividing.

There are two subtypes:

  • Small cell carcinoma: The cancer cells are small with very little cytoplasm and dark nuclei.

  • Large cell carcinoma: The cancer cells are larger with more cytoplasm and prominent nucleoli.

Both types show a high degree of atypia (abnormal features) and frequent cell division.

Other tests performed to confirm the diagnosis

Pathologists use a test called immunohistochemistry to confirm the diagnosis. This test uses special antibodies to detect proteins commonly produced by neuroendocrine cells. In poorly differentiated NEC, the tumor cells are typically positive for:

  • Synaptophysin.

  • Chromogranin A (may be weak or only focally positive).

  • CD56.

  • Ki-67 (a marker used to determine how fast the tumor is growing; usually very high in NEC).

These tests help distinguish NEC from other types of stomach cancer, such as adenocarcinoma.

WHO grade

All poorly differentiated neuroendocrine carcinomas are considered high grade (Grade 3 or G3). This is based on the number of dividing cells (mitotic figures) and the Ki-67 proliferation index:

  • Mitotic rate: More than 20 mitotic figures per 2 mm²

  • Ki-67 index: Greater than 20%, often much higher (over 60%)

This high grade means that the tumor is growing and spreading quickly.

Depth of invasion and pathologic tumour stage (pT)

Poorly differentiated neuroendocrine carcinoma (NEC) starts from cells in the innermost layer of the stomach called the mucosa. As the tumour grows, it can spread into deeper layers of the stomach wall and into nearby organs.

Pathologists determine the tumour stage (pT) by examining how far the tumour has grown into or beyond the stomach wall:

  • T1 – The tumour is limited to the mucosa or submucosa and is 1 cm or smaller.

  • T2 – The tumour is larger than 1 cm and has grown into the muscularis propria (a thick muscle layer).

  • T3 – The tumour has reached the subserosal tissue near the outer surface of the stomach.

  • T4a – The tumour has grown through the serosa (the outermost surface of the stomach).

  • T4b – The tumour has grown into nearby organs such as the pancreas, spleen, or colon.

Deeper invasion into the stomach wall or surrounding tissues is associated with a more advanced stage and a higher risk of the cancer spreading. Tumours at a higher pT stage often require more aggressive treatment.

Perineural invasion

Perineural invasion (PNI) means that cancer cells are growing along or around a nerve. This is considered an aggressive feature because it may help the cancer spread into nearby tissues. Pathologists look for this under the microscope, and if seen, the pathology report will describe PNI as “positive” or “present.” If no cancer cells are seen near nerves, the report will say “negative” or “absent.”

The presence of perineural invasion may influence treatment decisions, such as the need for chemotherapy or closer follow-up after surgery.

Lymphovascular invasion

Lymphovascular invasion (LVI) means that cancer cells are seen inside small blood vessels or lymphatic vessels near the tumour. These vessels are pathways the cancer can use to spread to other parts of the body, especially to lymph nodes, the liver, or lungs.

If LVI is found, it is reported as “present” or “positive.” If no tumour cells are seen in these vessels, the report will say “absent” or “negative.” The presence of LVI increases the risk of metastasis and may influence the need for additional treatment.

Margins

A margin is the edge or border of tissue removed during surgery. After surgery, a pathologist examines the margins under a microscope to see whether any cancer cells are present at the cut edge of the tissue.

For stomach tumours, the following margins may be described:

  • Proximal margin – The edge of the stomach closest to the esophagus.

  • Distal margin – The edge closest to the small intestine (duodenum).

  • Radial (serosal) margin – The outer surface of the stomach facing the abdominal cavity.

  • Deep margin – The base of the tumour, especially relevant in endoscopic resections.

A negative (clear) margin means no cancer cells were seen at the edge, suggesting the tumour was completely removed. A positive (involved) margin means cancer cells were found at the edge, which raises concern that some tumour may have been left behind. In some cases, the report may also describe how close the cancer cells were to the margin, even if the margin was negative.

Margins are important because they help determine whether further treatment is needed after surgery.

Lymph nodes

Lymph nodes are small immune structures that help filter fluids and trap abnormal cells. Cancer cells from a tumour in the stomach can travel to nearby lymph nodes through lymphatic vessels, a process called metastasis.

During surgery for poorly differentiated NEC, lymph nodes near the stomach are often removed to check for cancer spread. These lymph nodes may be located in:

  • The perigastric fat (fat surrounding the stomach).

  • Along the lesser or greater curvature of the stomach.

  • Around the celiac axis or peripancreatic area (especially for deeply invasive tumours).

Each lymph node is examined under a microscope by a pathologist to look for tumour cells. The lymph node is called positive if cancer is found and negative if no cancer is seen.

The number of positive lymph nodes is used to determine the pathologic nodal stage (pN):

  • pN0 – No cancer found in any lymph nodes.

  • pN1 – Cancer found in 1 or 2 lymph nodes.

  • pN2 – Cancer found in 3 to 6 lymph nodes.

  • pN3a – Cancer found in 7 to 15 lymph nodes.

  • pN3b – Cancer found in 16 or more lymph nodes.

  • pNX – No lymph nodes were submitted or evaluated.

Lymph node involvement is important because it increases the risk of the cancer spreading to other organs. It also helps guide decisions about additional treatment, such as chemotherapy or more frequent monitoring.

Questions to ask your doctor

  • What type of neuroendocrine carcinoma do I have?

  • Has the cancer spread to lymph nodes or other parts of the body?

  • Were the surgical margins clear of cancer?

  • What treatments are recommended for this type of cancer?

  • Will I need chemotherapy or radiation?

  • What follow-up care will I need after treatment?

A+ A A-