Poorly differentiated neuroendocrine carcinoma of the stomach

By Jason Wasserman MD PhD FRCPC
December 11, 2024

This article is designed to help you understand your pathology report for poorly differentiated neuroendocrine carcinoma (NEC) of the stomach. Each section explains an important aspect of the diagnosis and what it means for you.

What is a poorly differentiated neuroendocrine carcinoma?

A poorly differentiated neuroendocrine carcinoma (NEC) is an aggressive type of stomach cancer that starts in neuroendocrine cells. These cells, which are found throughout the body, help regulate various functions by producing hormones. Unlike well differentiated neuroendocrine tumours, poorly differentiated NECs grow rapidly, look very abnormal under the microscope, and are often diagnosed at an advanced stage.

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

The symptoms of poorly differentiated neuroendocrine carcinoma are often nonspecific and can include:

• Indigestion (dyspepsia) and weight loss caused by tumour growth or spread to other parts of the body.
• Bleeding from the stomach and anaemia due to tumour ulceration.
• Stomach pain from tumour growth or inflammation.
• Obstruction in the stomach, particularly if the tumour is located in the pyloric region.

These symptoms are often subtle at first but may worsen as the tumour grows or spreads.

What causes a poorly differentiated neuroendocrine carcinoma in the stomach?

The exact causes of poorly differentiated neuroendocrine carcinomas are not well understood. Unlike some other stomach cancers, no specific risk factors or environmental causes have been identified. However, a rare case of this tumour type has been linked to the Merkel cell polyomavirus, a virus that is also associated with Merkel cell carcinoma in other parts of the body.

How is this diagnosis made?

The diagnosis of poorly differentiated neuroendocrine carcinoma is made by examining a tissue sample taken from the stomach in a biopsy. A pathologist uses a microscope to look for the characteristic features of the tumour. Special tests, such as immunohistochemistry, may also be used to confirm the diagnosis and provide additional information about the tumour.

What are the microscopic features of poorly differentiated neuroendocrine carcinoma?

When viewed under the microscope, poorly differentiated neuroendocrine carcinomas of the stomach are made up of abnormal, rapidly dividing cells. These tumours are divided into two subtypes:

• Small cell neuroendocrine carcinoma (SCNEC): Small cell type neuroendocrine carcinoma of the stomach comprises small tumour cells with very little cytoplasm and dark, densely packed nuclei.
• Large cell neuroendocrine carcinoma (LCNEC): Large cell type neuroendocrine carcinoma of the stomach comprises larger cells with more cytoplasm and vesicular (open-looking) nuclei with prominent nucleoli.

Both subtypes show a high rate of cell division, with a mitotic count greater than 20 per square millimetre and a Ki-67 proliferation index often exceeding 60–70%.

Immunohistochemistry

Immunohistochemistry is a special test that uses antibodies to detect specific proteins in tumour cells. It is often used to confirm the diagnosis of poorly differentiated neuroendocrine carcinoma and to exclude similar-looking tumours.

For gastric neuroendocrine carcinomas, the tumour cells are typically positive for synaptophysin, a general marker of neuroendocrine cells. Chromogranin A may be absent or only focally present, often showing a dot-like staining pattern. Some tumours, particularly small cell neuroendocrine carcinomas, may also show positivity for markers such as TTF1 and ASH1L (ASH1), which are more commonly associated with lung tumours.

WHO grade

Poorly differentiated neuroendocrine carcinomas are classified as Grade 3 (G3) under the World Health Organization (WHO) system. This grade reflects their high rate of cell division and aggressive behaviour. Unlike well differentiated neuroendocrine tumours, poorly differentiated neuroendocrine carcinomas are always considered high grade.

Tumour extension

Poorly differentiated neuroendocrine carcinomas begin in the mucosa (stomach lining) and can grow deeper into the stomach wall.

The stomach has several layers:

1. Mucosa: The innermost layer where most tumours begin. The mucosa includes the epithelium, lamina propria, and muscularis mucosae.
2. Submucosa: A supportive layer beneath the mucosa.
3. Muscularis propria: A thick muscle layer that helps the stomach contract.
4. Subserosa and serosa: Outer layers that protect the stomach and separate it from nearby organs.

The depth of invasion is important because tumours that extend deeper into the stomach wall are more likely to spread to other organs or lymph nodes.

Margins

In pathology, a margin is the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.

Pathologists typically assess margins following a surgical procedure, like an excision or resection, that removes the entire tumour. Margins aren’t usually evaluated after a biopsy, which removes only part of the tumour. The number of margins reported and their size—how much normal tissue is between the tumour and the cut edge—vary based on the tissue type and tumour location.

Pathologists examine margins to check if tumour cells are at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some cancer may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.

Pathologic stage for poorly differentiated neuroendocrine carcinoma of the stomach

The TNM staging system describes how far the tumour has spread and guides treatment decisions.

T stage (tumour stage)

• T0: No tumour found.
• T1: Tumour is small and confined to the mucosa or submucosa.
• T2: Tumour invades the muscularis propria or is larger than 1 cm.
• T3: Tumour grows into the subserosa.
• T4: Tumour spreads to the serosa or nearby organs.

N stage (nodal stage)

• N0: No cancer in nearby lymph nodes.
• N1: Cancer found in nearby lymph nodes.

Staging helps determine the severity of the disease and guides treatment planning. Tumours with higher T and N stages are more advanced and may require more aggressive treatment.

What is the prognosis for a person diagnosed with a poorly differentiated neuroendocrine carcinoma of the stomach?

The prognosis for poorly differentiated neuroendocrine carcinoma is poor, with survival often measured in months rather than years. The aggressive nature of these tumours, combined with their tendency to be diagnosed at an advanced stage, contributes to this outlook. When these tumours are part of a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), the neuroendocrine carcinoma component and its high Ki-67 index largely determine the prognosis.