6 questions about cancer of the unknown primary (CUP)

Cancer is defined by where it starts and not by where it spreads. Where it starts helps determine how it’s treated and even the way people refer to it, such as with lung cancer, breast cancer or kidney cancer, to name a few. Even if cancer cells spread to other parts of the body – called metastatic disease – cancer is still treated based on where it first occurred.

But sometimes, the origin of metastatic cancer isn’t known. This is a diagnosis of cancer of the unknown primary (CUP). To learn how this type of cancer is diagnosed, how it’s treated and what research is underway to improve care of CUP patients, we spoke with Kanwal Raghav, M.D.

Where is cancer of the unknown primary found?

Cancer of the unknown primary is a rare group of metastatic cancers that are found after they’ve spread, but the location of the original tumor isn’t clear. These secondary tumors are most commonly found in the lungs, liver, lymph nodes and the bones. They can also be found in the lining of the bowel, which is called the peritoneum.

What are symptoms of cancer of the unknown primary?

The symptoms of CUP are like those of many other cancers. Patients may have unexplained weight loss, pain, loss of appetite, night sweats, fever and chills.

When patients experience these symptoms, they should talk with their doctor who will order tests to determine what’s going on. This work-up includes imaging, a biopsy and a series of tests called a molecular profile that reveal the genetic characteristics of the tumor cells. If we can’t determine the original source of the cancer cells, then patients are diagnosed with CUP. It’s only about 2% to 3% of patients with metastatic disease.

Why can’t the primary tumor be found?

Traditionally, it’s thought that a cancer grows from a few cells. It keeps growing and eventually spreads to other parts of the body. So one idea is that the primary lesions are so small that our tools aren’t sensitive enough to detect them. Years ago, this may have been true, but our imaging techniques are now very sophisticated and can find incredibly small suspicious spots anywhere in the body.

Another idea is that the immune system or other mechanisms within the body destroyed the primary tumor on its own. The scenario is that when the cancer cells started to spread throughout the body, they found better conditions to grow, so those are the tumors we see at initial diagnosis. The immune system naturally destroyed the initial cancer cells from the primary location, so we can’t find it anymore.

We can’t prove that hypothesis without knowing the true original location of the primary tumor, but it’s what I personally feel is going on with many of these patients.

How is cancer of the unknown primary treated?

Based on the clues gathered during the diagnostic work-up, plus other factors like the patient’s age, race, sex, health history, smoking status, occupational exposures and family history, we make an informed guess on where the original tumor was likely located. We then use our estimate to determine the best treatment approach. If we feel confident in our estimate, we can tailor the treatment to that suspected cancer type. If there is more uncertainty, we can offer the patient a combination of chemotherapies called empiric chemotherapy that are known to be effective across a few cancer types.

What should patients consider when deciding where to seek CUP treatment?

Any cancer diagnosis is overwhelming. But a diagnosis of cancer of the unknown primary brings added uncertainty, which can make it more challenging for both the patient and the providers.

That’s why it’s critical for patients to seek care from someone with the expertise to be able to differentiate one clue from the other when looking at a patient’s full work-up. The same clue in two different situations can mean very different things when determining the likely primary tumor and, therefore, the best treatment approach. This can also provide reassurance for patients that they are receiving a well-thought-out treatment plan guided by expertise and personalized for them.

How is research improving care of patients with cancer of the unknown primary?

Because CUP is so rare, research is difficult. But at MD Anderson, we see the most patients in the world with this diagnosis, so we’re able to pull from our experience to help drive desperately needed advances. Our research is centered around three aspects.

The biggest challenge that we’re working to overcome is determining accurate prognoses. Anticipating a patient’s survival is important because it determines the goals of care. It also helps determine the best treatment approach. Across many cancer types, a tool called a prognostic nomogram is used to predict patients’ survival. We’ve recently developed this tool for CUP and are in the process of publishing our work.

Secondly, at MD Anderson we strive for an individualized and personalized approach. Through our research, we have defined subsets of CUP. This allows us to fine-tune chemotherapy regimens and attempt therapy that’s specific to what we estimate to be the original tumor site. We also emphasize molecular profiling, which allows us to identify biomarkers that open the door to targeted therapies and even immunotherapy.

And, lastly, we’re working to offer more effective therapies. We’re looking at the latest treatment advances in other cancer types to see if those new therapies can fit into CUP treatment plans.   

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