Ductal adenocarcinoma of the pancreas

Jason Wasserman MD PhD FRCPC
January 28, 2025


Ductal adenocarcinoma, also called ductal carcinoma, is the most common type of pancreatic cancer. It starts in the pancreas from specialized cells lining small channels called ducts. These ducts help transport digestive enzymes produced by the pancreas. Ductal adenocarcinoma can develop in any part of the pancreas but is most often found in the part closest to the small intestine, known as the “head” of the pancreas. This aggressive type of cancer can spread quickly to nearby organs and the liver.

What are the symptoms of ductal adenocarcinoma of the pancreas?

Symptoms of ductal adenocarcinoma are often non-specific, meaning many conditions can cause them. Most people do not experience noticeable symptoms until the tumour has spread outside the pancreas. Possible symptoms include:

  • Loss of appetite.
  • Nausea.
  • Indigestion.
  • Back pain.
  • Fatigue.
  • Unexplained weight loss.
  • Jaundice (yellowing of the skin and eyes) is often a late symptom caused by a blockage of the bile duct.

What causes ductal adenocarcinoma of the pancreas?

There is no single known cause of ductal adenocarcinoma, but several factors increase the risk of developing this cancer. Smoking is the most important risk factor, which can increase the risk by two to three times.

Other risk factors include:

  • Obesity.
  • Lack of physical activity.
  • Diets high in saturated fats.
  • Diets low in fruits and vegetables.

How is this diagnosis made?

The diagnosis of ductal adenocarcinoma usually starts with a biopsy, where a small tissue sample is removed for testing. This may involve a fine needle aspiration biopsy (FNAB) or a core needle biopsy. If the biopsy confirms the diagnosis, surgery is often performed to remove the tumour. This surgery typically involves removing part of the pancreas along with nearby structures like the small bowel and stomach in a procedure called a “Whipple operation.”

Grade

Grade is a term used to describe how different the tumour cells in ductal adenocarcinoma look and behave compared to normal cells in the pancreas. The pathologist evaluates several features to assign a grade, including:

  • Glandular differentiation: This refers to how closely the tumour cells form gland-like structures similar to those found in normal pancreatic tissue. Tumours that form well-organized glands are usually considered “well differentiated,” while those with poorly organized or no gland formation are “poorly differentiated.”
  • Mucin production: Mucin is a jelly-like substance normally produced by the glands in the pancreas. Pathologists check how much mucin the tumour cells produce, which can provide clues about the tumour’s behaviour.
  • Mitotic activity: Mitosis is the process of cell division, and “mitotic activity” refers to how often the tumour cells divide. Tumours with more frequent cell division tend to grow and spread more aggressively.
  • Nuclear features: The nucleus is the control center of a cell. Tumour cells often have larger or irregularly shaped nuclei, and the degree of these changes helps determine the grade.

When a tumour shows variation in these features (called intratumoral heterogeneity), the highest grade is assigned, even if only a small part of the tumour appears more aggressive. For example, if most of the tumour is well differentiated but a small area is poorly differentiated, the overall grade will be based on the poorly differentiated area.

Using the above criteria, pathologists group ductal adenocarcinoma of the pancreas into one of the three following grades:

  • Well differentiated: The tumour cells resemble normal pancreatic cells, form organized glands, and have low mitotic activity. These tumours tend to grow and spread more slowly.
  • Moderately differentiated: The tumour cells differ slightly from normal cells and have a moderate level of mitotic activity.
  • Poorly differentiated: The tumour cells look very different from normal cells, form few or no glands, and have high mitotic activity. These tumours are more aggressive and more likely to spread.

Doctors use the grade to help predict how the tumour will behave and to guide treatment decisions. Studies show that higher-grade tumours are associated with worse survival outcomes, making the grade an independent factor in understanding a person’s prognosis.

Mismatch repair proteins

Mismatch repair proteins (MMR) are a system inside normal, healthy cells that fix mistakes in our genetic material (DNA). The system comprises different proteins, the four most common being MSH2, MSH6, MLH1, and PMS2. The four MMR proteins work in pairs to fix damaged DNA. Specifically, MSH2 works with MSH6, and MLH1 works with PMS2. If one protein is lost, the pair cannot function normally, and the risk of developing cancer increases.

How do pathologists test for mismatch repair proteins?

The most common way to test for mismatch repair proteins is immunohistochemistry. This test allows pathologists to see if the tumour cells produce all four mismatch repair proteins. The results of this test are typically reported as follows:

  • Normal result: Retained protein expression.
  • Abnormal result: Loss of protein expression.

Why is testing for mismatch repair proteins important?

Mismatch repair testing is important because it can help predict how well specific treatments may work. For instance, cancers with a loss of mismatch repair protein expression are more likely to respond to immunotherapy treatments like PD-1 or PD-L1 inhibitors. This is because the many mutations often found in deficient tumours can produce new antigens that make the tumour more visible and vulnerable to the immune system.

Mismatch repair testing is also performed to identify patients who may have Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). Lynch syndrome is a genetic disorder that increases the risk of developing various types of cancer, including esophageal cancer, colon cancer, endometrial cancer, ovarian cancer, and stomach cancer.

What does ductal adenocarcinoma of the pancreas look like under the microscope?

When pathologists examine ductal adenocarcinoma of the pancreas under the microscope, they see cancer cells forming gland-like structures that look similar to the normal ducts in the pancreas. However, these cancerous glands grow in a disorganized way, spreading into the surrounding pancreas and causing a reaction in the nearby tissue. This reaction, called desmoplasia, appears as dense, fibrous tissue around the cancerous glands and is a hallmark of this type of cancer.

In well differentiated tumours, the cancer cells form glands that closely resemble normal pancreatic ducts. These glands may look fairly regular but often have features that suggest cancer, such as:

  • Irregular shapes or branching patterns.
  • Glands breaking open and leaking mucin (a jelly-like substance) into the surrounding tissue.
  • Multiple layers of cells lining the glands instead of the single layer seen in normal ducts.
  • Clusters of immune cells, cellular debris (dead cells), or inflammation inside the gland openings.

In moderately differentiated tumours, the cancer cells still form glands, but these are more abnormal. Pathologists may see a mix of different gland shapes and patterns, such as cribriform (gland openings that resemble a sieve) or papillary (finger-like projections). At the edges of the tumour, the glands may become smaller and more irregular, and some cancer cells may appear individually.

Poorly differentiated tumours look very different from normal pancreas tissue. These tumours often consist of solid sheets of cancer cells without any recognizable gland structure. The cells may be pleomorphic (vary in size and shape) and may not produce much mucin. Areas of dead tissue (necrosis) and bleeding are common. These tumours tend to grow and spread more aggressively.

Tumor size

The tumour will be measured after it is removed. The size is important because it helps determine the tumour stage (pT). Larger tumours are often associated with a worse prognosis.

Tumour extension

The pancreas is located near many vital organs and tissues, including the liver, stomach, small intestine, and large blood vessels. Tumour extension refers to cancer cells spreading beyond the pancreas into these nearby structures. This information is included in your pathology report because it affects the tumour stage (pT) and is linked to the prognosis.

Pancreatic intraepithelial neoplasia (PanIN)

Ductal adenocarcinoma often begins as a pre-cancerous condition called pancreatic intraepithelial neoplasia (PanIN). In PanIN, abnormal cells are found inside the ducts but do not invade surrounding tissues. When these abnormal cells move into the surrounding tissue, the condition becomes ductal adenocarcinoma. This process is called invasion.

Perineural invasion

Perineural invasion occurs when cancer cells are found inside or around nerves. Nerves transmit signals, such as pain or temperature, between the body and the brain. Cancer cells can use nerves to spread to surrounding tissues, increasing the risk of tumour recurrence after surgery.

Perineural invasion

Lymphovascular invasion

Lymphovascular invasion means cancer cells are found inside blood vessels or lymphatic vessels. Blood vessels carry blood throughout the body, while lymphatic vessels carry a fluid called lymph to small immune organs called lymph nodes. Cancer cells can use these vessels to spread to other body parts, such as lymph nodes or distant organs.

Lymphovascular invasion

Margins

Margins refer to the edges of tissue removed during surgery. A negative margin means no cancer cells are found at the edge, while a positive margin means cancer cells are at the cut edge. Positive margins suggest that some cancer may have been left behind, and additional treatment, such as surgery or radiation therapy, may be needed.

Key margins in the pancreas include:

  • Common bile duct margin: The channel connecting the liver to the pancreas.
  • Pancreatic margin: The part of the pancreas that was cut to remove the tumour.
  • Other margins: These may include the uncinate process (part of the pancreas), duodenum (small bowel), and stomach.

Margin

Treatment effect

If you had chemotherapy or radiation therapy before surgery, your pathology report will describe how much of the tumour is still alive. This is called the treatment effect and is usually graded on a scale of 0 to 3, with 0 meaning no remaining cancer cells and 3 meaning little or no response to treatment.

Lymph nodes

Lymph nodes are small immune organs that cancer cells can spread to through lymphatic vessels. During surgery, nearby lymph nodes are often removed and examined. Your report will describe the total number of lymph nodes examined and how many contained cancer cells.

  • Positive lymph node: Contains cancer cells.
  • Negative lymph node: Does not contain cancer cells.

The number of lymph nodes with cancer is important for determining the nodal stage (pN) and prognosis.

Lymph node

Pathologic stage for ductal adenocarcinoma

The pathologic stage for ductal adenocarcinoma of the pancreas is determined using the TNM system, which stands for Tumour (T), Nodes (N), and Metastases (M). Each category is assigned a number:

Tumour stage (pT):

  • T1: Tumour is 2 cm or smaller.
  • T2: Tumour is larger than 2 cm but not larger than 4 cm.
  • T3: Tumour is larger than 4 cm.
  • T4: Tumour has spread into major nearby blood vessels.

Nodal stage (pN):

  • N0: No cancer cells in lymph nodes.
  • N1: Cancer cells in 1 to 3 lymph nodes.
  • N2: Cancer cells in 4 or more lymph nodes.

Prognosis

The prognosis for ductal adenocarcinoma of the pancreas is generally poor, making it one of the most challenging cancers to treat. Without treatment, the average survival time is only 3 to 5 months. Even with surgery, which is the most effective treatment, the average survival time increases to 10 to 20 months. Unfortunately, only 10 to 20% of patients are eligible for surgery at the time of diagnosis because most tumours are discovered too late.

The overall 5-year survival rate for all patients with ductal adenocarcinoma is about 8%. This improves slightly to 15–25% for those who undergo successful surgery. However, even after surgery, 70–90% of tumours return (recur) within two years, often in the pancreas, liver, peritoneal cavity, or nearby lymph nodes.

Factors that affect prognosis

  1. Stage of the cancer: The cancer stage at diagnosis is the most important predictor of survival. Patients whose tumours are small (less than 3 cm) and confined to the pancreas have a better prognosis than those with larger tumours or tumours that have spread beyond the pancreas.
  2. Resectability: The prognosis is better if the tumour can be completely removed during surgery (called an R0 resection). Tumours that involve major blood vessels or show cancer cells at the surgical margins (edges) are associated with a higher risk of recurrence.
  3. Lymph node involvement: Cancer cells in nearby lymph nodes significantly worsen the prognosis. Pathologists often calculate a lymph node ratio (the number of lymph nodes containing cancer cells divided by the total number of lymph nodes examined), which provides important information about the likelihood of recurrence and long-term survival.
  4. Location of the tumour: Tumours in the body or tail of the pancreas are often diagnosed at a more advanced stage than those in the head of the pancreas, making them harder to treat successfully.
  5. Tumour grade and microscopic features: High grade tumours (those with more abnormal-looking cells and higher rates of cell division) tend to behave more aggressively. Features like perineural invasion (cancer spreading along nerves) and vascular invasion (cancer spreading into blood vessels) also worsen the prognosis.
  6. Other factors:
    • Biomarkers: High levels of a tumour marker called CA19-9 are often linked to worse outcomes.
    • Genetic changes: Alterations in the SMAD4 gene in tumour cells are associated with poorer survival.
    • Obesity and race: These factors may also affect outcomes.
    • Metastases: Patients with metastases limited to the lungs tend to have better survival than those with metastases in other organs like the liver.

While chemotherapy and radiation therapy may help prolong survival, the improvement is often modest. These treatments are typically used before surgery (neoadjuvant therapy) to shrink the tumour or after surgery (adjuvant therapy) to reduce the risk of recurrence.

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