Written by Federico Citterich
Conceived and reviewed by Alessandro Rossetta
Pancreatic cancer only shows symptoms in advanced stages, yet early detection methods are still absent. What efforts have been made so far, and why haven’t they been successful?
Detecting pancreatic cancer is extremely challenging, as we discussed in our previous issue Pancreatic Cancer: An Invisible Killer. Unlike other forms of tumors, pancreatic cancer doesn’t present obvious early symptoms, and by the time these symptoms appear, the disease is often advanced. Additionally, the pancreas is located deep in the abdomen, making it hard to examine with non-invasive imaging. That’s why medical researchers have been trying to develop early screening methods to detect pancreatic cancer even when proper symptoms are still absent. Currently, however, there still is no accurate early detection method. Why? What has been done so far? And why didn’t it work?
Let’s start from the very beginning. X-rays and early forms of computed tomography (CT) scans were among the first methods used to detect pancreatic abnormalities. In the mid-20th Century, X-rays were widely used for abdominal imaging, however this technique couldn’t directly visualize internal organs. Instead, medical practitioners only used X-rays to detect indirect signs of pancreatic cancer, such as the displacement of nearby structures. Only the introduction of early CT scans, between the 1970s and 1980s, allowed for cross-sectional imaging, significantly improving pancreatic visualization. However, early CT scanners had a rather low resolution, making tumors – particularly small ones – still difficult to detect. Back then, CT was mostly used to confirm already suspected pancreatic cancer rather than as a screening tool.
CT scans combine multiple X-ray images taken from different angles to create cross-sectional (or “slice”) images of the body.
In the 1990s, the establishment of multi-detector CT (MDCT), CT scans with a significantly higher resolution, provided physicians with more detailed images with thinner slices. These devices, still used today, can detect tumors as small as 1-2 cm, highly improving tumor visualization. However, tumor of these sizes may still be too advanced for curative treatment. In fact, modern MDCT scans are still not effective for detecting microscopic early stage cancers, but are mainly used to diagnose pancreatic cancer when there is already clinical suspicion.
In the 1990s, simultaneously to the development of MDCT, Magnetic Resonance Imaging (MRI) was introduced in hospitals as well. MRI uses powerful magnets and radio waves to create detailed images of the body’s internal structures, including soft tissues. To do this, the device generates a strong magnetic field that temporarily aligns hydrogen atoms in the body, which are then disturbed by short bursts of radio waves. When the atoms return to their original state, they emit signals that are detected and processed into images. Still used today, MRI provides better soft tissue contrast than CT, and is utilized to detect cystic pancreatic lesions1 and evaluate pancreatic and bile ducts2. However, MRI still struggles to identify microscopic pancreatic cancer in its early stage. Moreover, some pancreatic cysts detected on MRI may never turn cancerous, leading to potentially significant numbers of false positives and unnecessary follow-ups. Additionally, MRI is significantly more expensive and time-consuming than CT, taking up to 60 minutes for a full scan and making it inefficient for routine, large-scale screening.
The main problem with both CT and MRI is the fact that none of them is able to identify pancreatic cancer in its very early stage, when it’s still only a few millimeters large. This is mainly due to the fact that the pancreas is located deep inside the abdomen, making external screening unable to provide a full picture of its state. This limitation was overcome when, at the beginning of the 21st Century, endoscopic ultrasound (EUS) was introduced. EUS is a procedure that combines the use of a flexible tube with a camera (endoscopy) and high-frequency sound waves (ultrasound) to produce precise images of internal structures. Unlike external ultrasound, which sends sound waves through the skin, EUS places the ultrasound probe directly inside the body, much closer to the organ that needs to be screened. In particular, the tube is inserted through the mouth of the patient and guided down the esophagus into the stomach. Once in position, the probe on the tube emits high-frequency sound waves, which bounce off surrounding tissues to create real-time, high-resolution images. If the system detects an abnormality, physicians can collect a sample of the tissue by passing a thin needle through the endoscope.
To perform an EUS, a camera-equipped endoscope is inserted in the patient’s mouth and pushed through the esophagus.
By placing the ultrasound probe right next to the body’s internal organs, EUC provides clearer, more detailed images than CT and MRI, and can detect tumors as small as 5mm. At first glance, this might make EUC appear to be the right method for early pancreatic cancer screening. However, this procedure has its downsides too. Unlike external imaging (CT and MRI), EUC is highly invasive and requires sedation or anesthesia. Endoscopic procedures also carry significant risks, including bleeding, infection, or perforation. And finally, EUS is very expensive due to the need for specialized equipment and highly trained gastroenterologists. Screening asymptomatic individuals for pancreatic cancer using EUS is unfeasible due to cost, patient burden, and risk of complications, and this technique is only utilized for high-risk individuals.
Therefore, previous technologies have downsides and, most importantly, are not sustainable in terms of time and operational costs for conducting mass screenings of at-risk populations. This is particularly true considering the increasing incidence of pancreatic cancer. Therefore, there is a need to develop a more cost-effective technology that is scalable and capable of providing early screening.
In the last decades, blood-based biomarkers emerged as a promising approach for the early detection of pancreatic cancer. A biomarker is a measurable molecule or characteristic produced by the body under certain conditions, such as when you have a particular disease. By tracking the presence of these molecules, medical practitioners can detect, diagnose, and monitor diseases.
In general, as tumors grow, they shed molecules into the bloodstream. Hence, looking for tumor-specific biomarkers in the blood can help researchers detect cancer, such as in the case of prostate-specific antigen (or PSA) for prostatic cancer. However, for some forms of cancer, such as breast or lung cancer, other detection methods are more reliable (e.g., mammography). For pancreatic cancer, contrarily, blood biomarkers provide a propitious alternative, because an effective early screening method is absent.
The most well-known biomarker for pancreatic cancer is Carbohydrate Antigen 19-9, or more simply CA 19-9. However, CA 19-9 is not specific enough, as it is also found in other pathological conditions. Therefore, it is not reliable for the early detection of pancreatic cancer and is primarily used to monitor disease progression in affected patients.
What’s CA 19-9?
CA 19-9 is a type of glycan (a sugar-based molecule) that forms when Lewis antigens, molecules found on cell membranes and involved in cell adhesion and regulation of immune response, undergo glycosylation – a biochemical process where sugar chains are attached to another molecule. This modification is overproduced in pancreatic cancer cells, leading to excessive CA 19-9 formation. However, this process also occurs naturally in epithelial cells – including those in the pancreas, liver, and bile ducts – and in other conditions, including liver diseases, gallbladder diseases, and other cancers (e.g., colorectal, gastric, ovarian). In other words, if detected, excessive CA 19-9 levels could signal either pancreatic cancer or other diseases, leading to false positives.
Schematic of the process of CA 19-9 formation.
Since CA 19-9 is unreliable for early detection, researchers have explored additional biomarkers, often in combination with CA 19-9, to improve accuracy. So far, however, scientists have been struggling to find specific enough biomarkers for pancreatic cancer. Most of these are in fact elevated also in non-cancerous conditions, leading to significant numbers of false positives. Since pancreatic cancer is relatively rare, a test must be extremely accurate to avoid too many false alarms. In addition, current biomarker tests often only detect advanced tumors rather than idetifying cancer at its earlier stage.
In light of this, and the points we’ve covered previously, early detection methods for pancreatic cancer are still largely absent due to several key challenges:
- Lack of symptoms in early stages:
Pancreatic cancer is often asymptomatic until it reaches advanced stages;
- Deep location of the pancreas:
The pancreas is located deep in the abdomen, making it difficult to examine with non-invasive imaging techniques;
- Limitations of imaging technologies:
CT scans, MRIs, and endoscopic ultrasounds can detect tumors but are not practical or cost-effective for screening asymptomatic individuals;
- Lack of reliable biomarkers:
Current blood tests (like CA19-9) are not specific or sensitive enough for early detection.
It really feels like researchers are hitting a dead end, and that the quest for a technology for the early detection of pancreatic cancer needs an extra push. But there is a glimmer of light at the end of the tunnel…
GLOSSARY
- Cystic pancreatic lesions are fluid-filled sacs in the pancreas that can be benign or potentially cancerous.
- Pancreatic and bile ducts are tubes that carry fluids; the pancreatic duct carries digestive enzymes from the pancreas, and the bile duct carries bile from the liver and gallbladder. Blockages, narrowing, or abnormalities in these structures can indicate the presence of tumors.
REFERENCES
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