Frank was a 50-year-old former professional athlete who worked for a sporting goods company. He continued to play sports recreationally and enjoyed good health until symptoms of “indigestion” prompted his physician to obtain abdominal ultrasound studies and then a CT scan. It showed a barely visible, 1 cm lesion deep in the head of the pancreas, and a needle biopsy confirmed that this was pancreatic cancer. He was referred for a Whipple procedure and appeared to be an excellent candidate for the possible surgical cure of his cancer due to its small size and the absence of any enlarged lymph nodes or signs of spread of disease on his scan. He was devastated by the diagnosis but was determined to be a survivor, saying, “Doc, we’re going to beat this, right?”
At surgery, there was no sign of a distant spread on my initial inspection of the abdomen. I performed a pylorus-sparing Whipple procedure that was uneventful. The pancreas appeared completely normal as the small cancer was nestled deep in the pancreatic head. We couldn’t see it or feel it. At the end of the procedure, as we were preparing to close the abdomen, I just happened to feel a small, BB-sized nodule in a suspensory ligament attached to the liver. The nodule was removed with a generous margin of normal tissue around it.
Post-operatively, Frank did well and recovered uneventfully, but the pathology report revealed that although his primary cancer was completely removed, and no lymph nodes were found to contain cancer cells, the BB-sized nodule was, in fact, a focus of metastatic pancreatic cancer. He underwent a full course of adjuvant chemo- and radiation therapy, which he tolerated well, but one year after surgery, a routine surveillance CT revealed multiple liver metastases. Despite aggressive chemotherapy, his disease rapidly progressed, and he died within six months.
The significance of tumor stage
Small tumors without evidence of spread to lymph nodes are thought to have the best chance of being cured surgically. Most tumors are graded or “staged” according to their size, whether their lymph nodes contain cancer cells and the presence or absence of metastatic disease. A Stage I tumor is less than 2 cm in diameter and is without lymphatic or distant spread. So Frank was thought to harbor a Stage I cancer and was told before the operation that the chance of his being cured by surgery would be in the range of 20-40% if the final pathology report confirmed this diagnosis. With the discovery of a focus of metastatic disease, however, his life expectancy dropped to 9-12 months due to the presence of Stage IV or metastatic disease. The removal of what appeared to be a single focus of tumor metastasis did not change his course and had we discovered the metastatic disease before starting the Whipple procedure. We would have abandoned the plan to remove half of his pancreas.
About 20% of patients who come to surgery with no evidence of tumor spread on x-ray are nonetheless found on careful exploration to harbor tumor metastases. This is why most surgeons perform a laparoscopic inspection of the abdomen before proceeding with a big incision and a big operation. We had performed the laparoscopic procedure on Frank but saw no sign of metastases. Frank’s tiny focus of metastatic tumor was buried within the fatty ligament that attaches the liver to the anterior abdominal wall, and it was discovered, just by chance, by palpating or feeling the tissue with my fingers. One of the drawbacks of laparoscopic surgery is the inability of the surgeon to actually feel the tissue, which limits the ability to detect small, unsuspected diseases
The insidious aspect of Frank’s case was that the tumor was already disseminated, spread distantly, away from the primary tumor, despite the absence of any detectable tumor cells in the lymph nodes that were removed along with the head of his pancreas. Lymph is the clear fluid that bathes all of the tissues in our bodies. The lymph collects in channels which eventually make their way to lymphatic ducts – larger channels – that eventually drain into the bloodstream. Lymph nodes or lymph glands are small, usually pea-sized nodules of cells that are part of the immune system and found along the lymph channels. The “lymphatic spread” of cancer cells, where cancer cells travel to the lymph nodes, is a common route of spread but not the only one. Pancreatic cancer cells are also known to climb up nerves that connect the pancreas to the nervous system that controls pancreatic function, and this “neurogenic spread” is an ominous characteristic of the most aggressive pancreatic cancers. Eventually, these cancer cells invade the blood vessels which supply the nerves, and the cancer cells enter the circulation. Some cancer cells have been seen to invade right through the wall of a blood vessel, and this “hematogenous spread” by direct invasion is also seen in pancreatic ductal adenocarcinoma or PDAC. Finally, some cancer cells just seem to fall off the primary tumor-like leaves off a tree and can be found in the abdominal cavity. Stage I tumors, or those classified as Stage IA, smaller than 1 cm, are the least likely to shed their cells by any method, but the risk is never zero.
The role of Circulating Tumor Cells or CTCs
Finding circulating tumor cells, or CTCs, in the blood of cancer victims has been a focus of researchers for decades. The CTCs are identified as cancer cells by the presence of specific proteins produced by these cells. They can be recovered from a blood sample when their number or concentration is high enough, or the detection technique is sensitive enough. The first discovery of CTCs was made in breast cancer patients over 50 years ago, but the routine use of this method had to await better methods to collect and identify the cells. Recently, the ability to recover CTCs in pancreatic cancer was confirmed, and more importantly, CTC’s were found to be detectable (in animals) even when the tumor is at an early or pre-invasive stage. Most recently, CTCs originating from patients with PDAC have been recovered and identified in the blood of the portal vein, which drains the pancreas.
This discovery is a major advance as it suggests that CTCs don’t appear in the bloodstream only when the tumor is metastatic but may be detectable when the tumor is still curable. The discovery also suggests that the metastatic activity of the tumor can be monitored by sampling CTCs, or detecting their absence, in the bloodstream. Finally, it provides oncologists with a method to sample the cells to see how or if the cancer cells are mutating to make themselves resistant to drug therapy. More research is needed to determine the best way of harvesting CTCs and confirm that these cells can detect pancreatic cancer early enough so that it can be cured by surgical removal of the tumor. Another approach is to harvest the DNA that is shed by tumor cells and is present in the bloodstream. The amount of tumor DNA, like the number of CTCs, may allow better treatment decisions and permit the discovery of tumors which are truly curable. These are hugely important goals and are the subject of current studies.
So despite Frank’s small cancer, his tumor had shed enough cancer cells to result in a tiny focus of metastatic disease, which we discovered almost by accident. The early shedding of cancer cells accounts for the fact that most patients who undergo what is thought to be a “curative resection” of their pancreatic cancer soon develop signs of distant spread when the metastatic disease grows enough to be seen on x-ray. Sampling the blood for CTCs or tumor DNA may provide a better way to determine who is actually likely to be cured by surgery, indicating the best treatment for a patient. It also provides a method to determine whether the administration of chemotherapy before removing the tumor, called neoadjuvant treatment, will increase the chances of a cure. These kinds of research studies are now underway.