Adenocarcinoma of the small intestine

by Jason Wasserman MD PhD FRCPC
November 8, 2024

Adenocarcinoma is the most common type of cancer in the small intestine (also known as the small bowel). It develops in the lining of the small intestine, the part of the digestive system that absorbs nutrients from food. Because the small intestine is a long, narrow structure deep within the body, this type of cancer can be challenging to detect early. Adenocarcinoma of the small intestine often grows slowly, but as it progresses, it can spread to nearby lymph nodes and other body parts.

Anatomy of the small intestine

The small intestine is a long, coiled tube that connects the stomach to the large intestine and comprises three main sections: the duodenum, jejunum, and ileum. The duodenum, located closest to the stomach, is where most small intestine adenocarcinomas occur, likely due to stomach acid and bile exposure. However, adenocarcinoma can also arise in the other parts of the small intestine, the jejunum and ileum, although these cases are less common.

What are the symptoms of adenocarcinoma of the small intestine?

Adenocarcinoma of the small intestine often does not cause symptoms early in the disease, making it difficult to diagnose. Many people may not know they have the disease until it has progressed.

As the cancer advances, it may cause symptoms that include:

• Abdominal pain is present in about two-thirds of patients at diagnosis.
• Occult bleeding means small amounts of blood in the stool that are not visible to the eye but can be detected with special tests.
• Blockage, or obstruction, of the intestine can cause severe abdominal pain, nausea, and vomiting. It occurs in around 40% of cases and is more common when the tumour is in the middle or lower parts of the small intestine (the jejunum or ileum).
• Bleeding can happen in approximately 24% of cases and may lead to weakness, fatigue, or anaemia (low red blood cell levels).

In some advanced cases, the tumour can cause adhesions, which are bands of tissue that stick different parts of the intestine together, making it more challenging to treat. Diagnosis often involves imaging tests such as CT scans, upper endoscopy, small-bowel barium transit, or surgery to locate and examine the tumour.

What risk factors are associated with developing adenocarcinoma of the small intestine?

Several factors increase the risk of developing adenocarcinoma in the small intestine:

• Chronic inflammatory conditions: Long-term inflammation, such as that caused by Crohn’s disease or celiac disease, can increase the risk of small intestine adenocarcinoma.
• Exposure to an unusual environment in the intestine: Certain surgeries, like creating an ileal conduit or reservoir, expose the small intestine to fluids it normally wouldn’t encounter, raising cancer risk.
• Location in the small intestine: Adenocarcinoma more often develops in the first part of the small intestine, called the duodenum, especially near the ampulla or pylorus (areas that connect to the stomach and bile ducts). The acid and bile in these areas are thought to contribute to the risk.
• Lifestyle factors: Smoking, alcohol consumption, and specific diets have been linked to a higher risk of this cancer.

Some hereditary genetic conditions also raise the risk:

• Familial adenomatous polyposis (FAP): A condition that causes polyps (small growths) to develop, primarily in the duodenum, which can progress to cancer.
• Lynch syndrome: A genetic condition that increases the risk of various cancers, including small intestine adenocarcinoma, due to the loss of specific mismatch repair proteins in cells.
• Peutz-Jeghers syndrome: A genetic disorder with a high risk of small intestine cancer, especially in the jejunum.

How is this diagnosis made?

Diagnosis of adenocarcinoma in the small intestine is usually made through a combination of imaging studies and tissue sampling. Initially, imaging tests like a CT scan, MRI, or small-bowel barium study can help locate a suspicious area within the small intestine. An endoscopic procedure, such as an upper endoscopy or capsule endoscopy (where a small camera is swallowed), may be used to examine the small intestine’s lining directly.

If a tumour is found, a biopsy is typically performed to collect a small tissue sample. This tissue is then examined under a microscope by a pathologist, who can confirm the diagnosis of adenocarcinoma and assess its features, such as the depth of invasion and any specific microscopic characteristics. In some cases, additional tests, such as immunohistochemistry, may be performed to help distinguish adenocarcinoma from other types of cancer.

Microscopic features

Under the microscope, adenocarcinoma of the small intestine typically shows abnormal gland-like structures formed by cancerous cells. These cells often vary in shape and size and can have large, irregular nuclei (the central part of the cell that contains DNA). In some cases, the tumour may produce mucus, which can fill spaces within the tumour. Pathologists examine these features closely to confirm the diagnosis and understand the tumour’s behaviour.

Histologic grade

Adenocarcinoma of the small intestine is divided into three grades – well differentiated, moderately differentiated, and poorly differentiated. The grade is based on the percentage of the tumour cells forming round structures called glands. A tumour that does not create any glands is called undifferentiated. The grade is important because poorly differentiated and undifferentiated tumours tend to behave more aggressively; for example, these tumours are more likely to spread to lymph nodes and other parts of the body.

• Well differentiated: More than 95% of the tumour comprises glands. Pathologists also describe these tumours as grade 1.
• Moderately differentiated: 50 to 95% of the tumour comprises glands. Pathologists also describe these tumours as grade 2.
• Poorly differentiated: Less than 50% of the tumour comprises glands. Pathologists also describe these tumours as grade 3.
• Undifferentiated: Very few glands are seen anywhere in the tumour.

Tumour extension

Adenocarcinoma of the small intestine begins in the mucosa, the innermost layer of the small intestine. The mucosa comprises two parts: the epithelium and the lamina propria. The epithelium is the thin layer of cells lining the inner surface, where the tumour first develops. Beneath the epithelium is the lamina propria, a layer containing connective tissue, blood vessels, and immune cells.

To diagnose adenocarcinoma, the tumour must invade beyond the epithelium into at least the lamina propria. A tumour that only involves the epithelium is called high grade dysplasia. As the tumour grows, it can spread further into deeper layers of the intestinal wall, including:

1. Submucosa – a supportive layer with more connective tissue and blood vessels.
2. Muscularis propria – a thick muscle layer that moves food along the intestine.
3. Serosa – the outermost layer, which acts as a protective covering.

The extent of tumour invasion into these layers is crucial for determining the cancer’s pathologic stage (pT). Tumours that invade only the upper layers tend to have a better outlook, while those that reach deeper layers or spread beyond the intestinal wall are more likely to affect nearby organs and lymph nodes. This depth of invasion helps guide treatment and predict the tumour’s behaviour.

Perineural invasion​

Pathologists use the term “perineural invasion” to describe a situation where cancer cells attach to or invade a nerve. “Intraneural invasion” is a related term that refers explicitly to cancer cells found inside a nerve. Nerves, resembling long wires, consist of groups of cells known as neurons. These nerves, present throughout the body, transmit information such as temperature, pressure, and pain between the body and the brain. Perineural invasion is important because it allows cancer cells to travel along the nerve into nearby organs and tissues, raising the risk of the tumour growing back after surgery.

Lymphovascular invasion​

Lymphovascular invasion occurs when cancer cells invade a blood vessel or lymphatic vessel. Blood vessels are thin tubes that carry blood throughout the body, whereas lymphatic vessels carry a fluid called lymph instead of blood. These lymphatic vessels connect to small immune organs scattered throughout the body, known as lymph nodes.

Lymphovascular invasion is important because it spreads cancer cells to other body parts, including lymph nodes or the liver, via the blood or lymphatic vessels. In addition, the presence of cancer cells inside a large vein beyond the wall of the colon (outside of the thick bundle of muscle) is associated with a high risk that the cancer cells will eventually be found in the liver.

​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, which 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.

What does it mean if the tumour shows signet ring cell features?

If the tumour has signet ring cell features, some cancer cells are large and filled with mucus, pushing the cell’s nucleus to one side and giving it a ring-like appearance. These cells are also dyscohesive, meaning they do not stick together. Tumours with these features can sometimes behave more aggressively, meaning they might spread quickly or be more challenging to treat.

What does it mean if the tumour shows mucinous features?

If a tumour has mucinous features, it means that the cancer cells produce a lot of mucus. This mucus collects in and around the cells, forming a jelly-like substance in the tumour. Mucinous features are sometimes associated with a higher risk of the cancer spreading to nearby areas. A tumour that is made up of more than 50% mucus-producing cells is called mucinous adenocarcinoma.

What does it mean if the tumour shows squamous differentiation?

Squamous differentiation means that some cancer cells resemble squamous cells, which are flat cells typically found in areas like the skin or the lining of specific organs such as the esophagus. This feature is unusual in adenocarcinomas of the small intestine. Squamous differentiation can sometimes suggest that the cancer may grow more aggressively or respond differently to treatment.

Lymph nodes​

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to these nodes via lymphatic vessels, prompting doctors to remove and examine them for cancer. This process is known as metastasis. Typically, cancer cells first migrate to lymph nodes nearest to the tumour, but more distant nodes can also be affected. Surgeons often remove the closest lymph nodes first and may take additional ones if they appear enlarged and potentially cancerous.

Pathologists examine the removed lymph nodes, reporting results as “positive” if cancer cells are found and “negative” if not. If cancer is detected, the report may indicate the size of the largest cluster, called a “focus” or “deposit.” Extranodal extension refers to tumour cells breaking through the lymph node’s outer capsule into nearby tissue.

Examining lymph nodes is important for determining the pathologic nodal stage (pN) and gauging the risk of cancer spreading to other body parts. This information aids doctors in deciding if further treatments, such as chemotherapy, radiation, or immunotherapy, are necessary.

Pathologic stage of adenocarcinoma of the small intestine

The pathologic stage of adenocarcinoma of the small intestine is determined by examining how deeply the tumour has invaded the layers of the small intestine, whether it has spread to nearby lymph nodes, and if there is any evidence of spread to distant parts of the body. This staging information helps doctors understand how advanced the cancer is and guides treatment planning.

The staging system used is known as the TNM system, where:

• T describes how far the tumour has grown into the layers of the small intestine.
• N describes whether the cancer has spread to nearby lymph nodes.
• M indicates if the cancer has spread (metastasized) to distant organs.

Here is a simplified breakdown of the T and N categories:

• T Categories:
  • pT0: No tumour is detected in the small intestine.
  • pTis: The tumour is limited to the inner lining, showing early cancerous changes (carcinoma in situ or high-grade dysplasia).
  • pT1: The tumour has grown into the first layers beneath the lining:
    • pT1a: Tumour is limited to the lamina propria, a thin layer of tissue just beneath the inner lining.
    • pT1b: Tumour extends into the submucosa, a layer containing blood vessels and connective tissue.
  • pT2: The tumour has grown into the muscularis propria, the thick muscle layer that helps move food.
  • pT3: The tumour has penetrated through the muscularis propria into a layer called the subserosa or nearby connective tissues but has not broken through the outer layer (serosa).
  • pT4: The tumour has either broken through the serosa (the outermost layer) or invaded nearby organs or structures, such as other parts of the small intestine, the pancreas, or bile ducts.
• N Categories:
  • pN0: No cancer is found in nearby lymph nodes.
  • pN1: Cancer has spread to one or two nearby lymph nodes.
  • pN2: Cancer has spread to three or more nearby lymph nodes.

This staging is a collaborative process. The pathologist provides detailed information on the tumour’s size and spread to nearby tissues and lymph nodes. Your doctors will then use this information and other test results to determine the final stage, which is essential for developing a treatment plan and predicting the likely outcome.