Well Differentiated Neuroendocrine Tumour of the Large Intestine: Understanding Your Pathology Report

by Ipshita Kak MD FRCPC
April 3, 2026

A well-differentiated neuroendocrine tumour (NET) is a type of tumour that starts from specialized neuroendocrine cells in the lining of the colon or rectum. Neuroendocrine cells are found throughout the digestive tract and help regulate functions such as digestion by releasing hormones in response to nervous system signals. When these cells grow abnormally, they form a neuroendocrine tumour.

Well-differentiated neuroendocrine tumors are called “well-differentiated” because the tumour cells appear organized and closely resemble normal neuroendocrine cells under the microscope. This is what distinguishes them from poorly differentiated neuroendocrine carcinoma, which is a much more aggressive cancer with very abnormal-looking cells and a very different treatment approach.

Well-differentiated neuroendocrine tumors can form anywhere in the colon or rectum, but are considerably more common in the rectum, where most are small and discovered incidentally during colonoscopy. Most grow slowly and remain confined to the bowel wall for many years. However, some — particularly those in the colon, larger tumors, and higher-grade tumors — can spread to lymph nodes or other organs. For this reason, all well-differentiated neuroendocrine tumors of the colorectum are considered cancerous, though they are usually far less aggressive than conventional colorectal adenocarcinoma.

Is a well-differentiated neuroendocrine tumour the same as cancer?

Yes. Well-differentiated neuroendocrine tumors are considered a form of cancer because they have the potential to grow and spread to other parts of the body. However, this type of cancer is usually far less aggressive than other forms of colorectal cancer. Many small, low-grade tumors — particularly those in the rectum — are cured by complete local removal and never require additional treatment. The risk of spread depends on the tumour’s size, grade, and location, and your doctor will use this information to determine what monitoring or treatment is appropriate for you.

What are the symptoms?

Many well-differentiated neuroendocrine tumors of the colon and rectum cause no symptoms at all. They are often found by chance during a colonoscopy performed for other reasons, such as cancer screening or investigation of unrelated symptoms. When symptoms are present, they may include rectal bleeding or blood in the stool, a change in bowel habits such as constipation or diarrhea, abdominal pain or discomfort, or a feeling of pressure or fullness in the rectum.

Rarely, if a tumour produces and releases hormones in large amounts, it can cause a group of symptoms known as carcinoid syndrome — including episodes of skin flushing, diarrhea, and wheezing. This is very uncommon in colorectal neuroendocrine tumors and is more typically seen when the tumour has spread to the liver.

What causes a well-differentiated neuroendocrine tumour?

The exact cause of most colorectal neuroendocrine tumors is not known. Most cases appear to develop by chance without a clear identifiable trigger. However, a small number of neuroendocrine tumors arise in the setting of inherited genetic syndromes, the most important of which include:

• Multiple endocrine neoplasia type 1 (MEN1) — An inherited condition caused by mutations in the MEN1 gene that significantly increases the risk of neuroendocrine tumors in the gastrointestinal tract, pancreas, and parathyroid glands.
• Von Hippel-Lindau (VHL) disease — An inherited syndrome associated with neuroendocrine tumors of the pancreas and, less commonly, other sites.
• Neurofibromatosis type 1 (NF1) — An inherited condition associated with neuroendocrine tumors in the small intestine and other areas of the gastrointestinal tract.

If your doctor suspects an inherited syndrome, they may recommend genetic counseling. Most people diagnosed with a colorectal neuroendocrine tumour, however, have no known inherited risk factor.

How is the diagnosis made?

The diagnosis is usually made after a tissue sample is taken during a colonoscopy — either as a biopsy or as part of a polypectomy — and examined under the microscope by a pathologist. If you received your diagnosis during a colonoscopy, our guide to understanding your colonoscopy biopsy report may also be helpful.

Under the microscope, well-differentiated neuroendocrine tumors have a distinctive appearance. The tumour cells are relatively uniform in size and shape, with round or oval nuclei containing a characteristic speckled pattern known as “salt and pepper” chromatin. The cells are arranged in organized structures such as nests, cords, trabeculae, or ribbons — a pattern that reflects their neuroendocrine origin. This appearance is very different from adenocarcinoma, which forms disorganized glands and has much more irregular cells.

To confirm the diagnosis, the pathologist performs immunohistochemistry, a specialized laboratory test that uses antibodies to detect proteins characteristic of neuroendocrine cells. Neuroendocrine markers commonly tested include synaptophysin, chromogranin A, and INSM1. A positive result for one or more of these markers, combined with the characteristic microscopic appearance, confirms the diagnosis.

Tumour grade

Grade is one of the most important features of a well-differentiated neuroendocrine tumour. It describes how quickly the tumour cells are dividing and growing, and it is a key predictor of how the tumour will behave.

To determine the grade, the pathologist counts the number of cells caught in the act of dividing under the microscope — these are called mitotic figures — and also measures the Ki-67 labeling index, which is the percentage of tumour cells that are actively preparing to divide. Both measurements together determine the grade:

• Grade 1 (G1) — Fewer than 2 mitotic figures per 10 high-power fields AND a Ki-67 index below 3%. The tumour is growing slowly. This is the most common grade for rectal NETs and carries an excellent prognosis when the tumour is small and confined.
• Grade 2 (G2) — Between 2 and 20 mitotic figures per 10 high-power fields OR a Ki-67 index of 3–20%. The tumour is growing at a moderate rate and carries a higher risk of spread than G1 tumors.
• Grade 3 (G3) — More than 20 mitotic figures per 10 high-power fields OR a Ki-67 index above 20%. The tumour is growing more rapidly. A G3 well-differentiated NET is still distinct from a poorly differentiated neuroendocrine carcinoma — it still has organized-looking cells and a different biology — but it requires close monitoring and often more aggressive treatment.

When the mitotic count and Ki-67 index point to different grades, the pathologist uses the higher of the two values to assign the final grade. Your pathology report will state the grade and typically include both the mitotic count and Ki-67 result so your medical team can interpret them together.

Level of invasion

Invasion refers to how deeply the tumour has grown into the wall of the colon or rectum. Well-differentiated neuroendocrine tumors begin from neuroendocrine cells in the innermost lining (the mucosa) and can extend into progressively deeper layers:

• Mucosa — the innermost lining where the tumour originates
• Submucosa — the supportive tissue layer just beneath the mucosa
• Muscularis propria — the thick muscle layer that moves stool through the colon
• Pericolorectal tissues — fatty tissue surrounding the outer wall of the colon and rectum
• Serosa — the outermost surface layer (present in some parts of the colon but not others)
• Adjacent organs — in advanced cases, the tumour may grow directly into nearby structures

The deepest layer the tumour has reached is reported as the level of invasion and contributes to the pathologic tumour stage (pT). Tumors that grow deeper into the wall are more likely to spread to lymph nodes or other organs.

Perineural invasion

Perineural invasion means that tumour cells are growing along or around a nerve. Nerves run throughout the colon and rectum, and tumour cells can use them as a pathway to reach surrounding tissues beyond the main tumour mass. Perineural invasion is associated with a higher risk of recurrence after treatment. Your pathology report will state whether this feature was identified.

Lymphovascular invasion

Lymphovascular invasion means that tumour cells have entered small blood vessels or lymphatic channels in the tissue around the tumour. Once inside these channels, tumour cells can travel to nearby lymph nodes or more distant organs. The presence of lymphovascular invasion is associated with a higher risk of spread and is considered when deciding how closely to monitor the tumour after treatment. Your report will state whether lymphovascular invasion was identified.

Surgical margins

A margin is the edge of the tissue removed during surgery or endoscopy. The pathologist examines the margin surfaces to determine whether tumour cells are present at the cut edge.

• Negative margin — No tumour cells are present at the cut edge. This suggests the tumour was completely removed, and this is the goal of any resection.
• Positive margin — Tumour cells are present at the cut edge, meaning some tumour may remain in the body. This may lead to a recommendation for additional removal, closer surveillance, or further treatment.

Margin status is particularly important for small rectal NETs removed endoscopically, where complete removal is often curative. If a tumour is found to have a positive margin after initial endoscopic removal, a repeat endoscopic procedure or surgical resection is usually recommended.

Tumour deposits

Tumour deposits are small clusters of tumour cells found in the fatty tissue surrounding the colon or rectum, separate from the main tumour and outside any lymph node structure. Their presence indicates local spread beyond the tumour mass and is considered an adverse prognostic feature. When tumour deposits are identified, this information is included in the pathology report and factored into staging and treatment planning.

Lymph nodes

Lymph nodes are small immune organs that can trap and filter tumour cells as they spread through the lymphatic system. When surgery is performed for a colorectal neuroendocrine tumour, nearby lymph nodes are typically removed along with the tumour and examined by the pathologist.

Your report will state the total number of lymph nodes examined and how many, if any, contain tumour cells. Lymph nodes are described as positive if tumour cells are present and negative if they are not. Lymph node involvement is used to determine the nodal stage (pN) and is one of the strongest predictors of whether the tumour is likely to spread further. When cancer is found in a lymph node, the report may also note whether the tumour has broken through the outer wall of the node — a finding called extranodal extension.

Biomarker and molecular testing

Molecular testing is less central to the workup of colorectal well-differentiated neuroendocrine tumors than it is for colorectal adenocarcinoma. Still, certain tests may appear in your report or be ordered as part of your care.

Somatostatin receptor expression (SSTR2)

Most well-differentiated neuroendocrine tumors express a surface protein called somatostatin receptor 2 (SSTR2). This protein can be detected by immunohistochemistry, and its presence is important for two reasons. First, SSTR2-positive tumors can be identified on a specialized nuclear medicine scan called somatostatin receptor scintigraphy (such as a Gallium-68 DOTATATE PET scan), which is used to assess disease throughout the body. Second, SSTR2 expression predicts that the tumour may respond to somatostatin analog medications (such as octreotide or lanreotide), which can slow tumour growth and control hormone-related symptoms in advanced disease. Your report may note whether SSTR2 expression was tested and the result.

Ki-67 labeling index

The Ki-67 labeling index is already used to determine tumour grade (see above), but it is also a biomarker in its own right. The specific Ki-67 percentage reported in your pathology report is important for treatment decisions in advanced or metastatic disease, where higher values are associated with faster tumour growth and may influence the choice of systemic therapy.

Hereditary syndrome testing

In patients with a personal or family history suggesting an inherited neuroendocrine tumour syndrome — such as MEN1, VHL, or NF1 — genetic testing or referral to a genetics specialist may be recommended. While most colorectal neuroendocrine tumors are sporadic (not inherited), identifying an underlying syndrome has important implications for the patient and their family members, who may need screening for related tumors in other organs.

For more information on molecular testing for neuroendocrine tumors, visit our Biomarkers and Molecular Testing section.

Pathologic stage (pTNM)

The pathologic stage describes how far the tumour has spread at the time of surgery. Well-differentiated uroendocrine tumors of the colon and rectum are staged using a specific TNM system developed for colorectal neuroendocrine tumors, based on the American Joint Committee on Cancer guidelines. Importantly, this system uses both tumour size and depth of invasion to assign the T stage, which differs from the staging system used for colorectal adenocarcinoma (which is based on depth alone) and from the system used for poorly differentiated neuroendocrine carcinoma (which uses the adenocarcinoma system).

Tumour stage (pT)

• pT1 — The tumour is 2 cm or smaller and has grown no deeper than the submucosa.
• pT2 — The tumour is larger than 2 cm, OR has grown into the muscularis propria (muscle layer), OR shows lymphovascular or perineural invasion.
• pT3 — The tumour has grown through the muscularis propria into the pericolorectal fat or tissues.
• pT4 — The tumour has reached the outer surface of the colon (serosa/visceral peritoneum) or has grown directly into a nearby organ or structure.

Nodal stage (pN)

• pN0 — No cancer found in any lymph nodes examined.
• pN1 — Cancer found in one or more regional lymph nodes.
• pNX — Lymph nodes were not assessed.

What is the prognosis for a well-differentiated neuroendocrine tumour?

The prognosis for well-differentiated neuroendocrine tumors of the colorectum depends strongly on the tumor’s location, size, grade, and whether it has spread.

Rectal neuroendocrine tumors make up the majority of colorectal NETs and generally have an excellent prognosis. Small rectal NETs (under 1 cm) that are grade 1 and completely removed endoscopically are almost always cured and rarely recur. Even with a longer follow-up of 20 years or more, many patients with low-stage rectal NETs remain free of disease. Larger tumors (over 2 cm) or those with lymphovascular invasion, deep invasion, or lymph node involvement carry a meaningfully higher risk of recurrence and metastatic spread.

Colon neuroendocrine tumors are less common and tend to present at a more advanced stage, with a higher proportion showing lymph node involvement at the time of diagnosis. For this reason, the prognosis for colon NETs is generally less favorable than for rectal NETs of comparable size and grade, and closer follow-up and more extensive surgery are often recommended.

In all cases, tumour grade is a critical prognostic factor: G1 tumors have the most favorable outlook, G2 tumors carry a higher risk, and G3 well-differentiated NETs — while still distinct from poorly differentiated neuroendocrine carcinoma — require more intensive management. Your treatment team will use all of the information in your pathology report to give you the most accurate assessment of your individual situation.

Questions to ask your doctor

Your pathology report contains important information that will guide your care. The following questions may help you prepare for your next appointment.

• Was the tumour completely removed with negative margins?
• What is the grade of my tumour, and what does that mean for how it is likely to behave?
• What is the pathologic stage — has the tumour spread to lymph nodes or other organs?
• Were any high-risk features found, such as lymphovascular invasion, perineural invasion, or a size greater than 2 cm?
• Does my tumour express somatostatin receptors, and would a DOTATATE PET scan be useful for assessing read?
• Do I need any additional surgery or endoscopic treatment?
• Should I be referred to a specialist in neuroendocrine tumors?
• Do I need genetic testing or counseling to look for an inherited condition such as MEN1?
• What follow-up tests and imaging will I need, and how often?
• Are there any symptoms I should watch for that might suggest the tumour has spread or returned?