Cancer of Unknown Primary (CUP) – What If There Are Metastases, but We Don’t Know Where the Cancer Started?
In most cancers, we first determine where the tumor originated and then assess whether it has spread to other parts of the body. For example, lung cancer that has spread to the liver is still treated as lung cancer, not as liver cancer.
However, sometimes the opposite occurs: a biopsy confirms that a patient has metastatic cancer, but despite a detailed diagnostic work-up, the site where the cancer originally developed cannot be identified. This condition is known as cancer of unknown primary, or CUP (Cancer of Unknown Primary). CUP is not a single specific type of cancer, but rather a group of different cancers that share one defining feature: at the time of diagnosis, their primary site is unknown.
How is it possible to find a metastasis but not the primary tumor?
At first glance, this may seem unusual. If a tumor has managed to produce metastases, how can we be unable to find the tumor from which they originated? There are several possible explanations.
The primary tumor may be very small and difficult to detect using available imaging methods. In some cases, it may be located in an area where it is difficult to identify. Sometimes metastatic cells grow considerably faster than the primary tumor itself, so it is the metastasis that first causes symptoms and leads to the diagnosis.
It is also possible that the immune system has stopped or eliminated a very small primary tumor after some of its cells had already spread to other organs.
In some patients, the primary site is identified later during follow-up. In that case, the disease is no longer considered CUP, and treatment can be adjusted according to the identified type of cancer.
How is CUP usually discovered?
Patients usually do not see a doctor because they have “CUP,” but because of symptoms caused by metastases.
Symptoms depend on where the disease is located and may include:
enlarged lymph nodes
pain, particularly in the bones or abdomen
weight loss and loss of appetite
significant fatigue and weakness
cough or difficulty breathing
accumulation of fluid in the abdomen or around the lungs
abnormalities in laboratory test results.
Imaging may then reveal, for example, a tumor lesion in the liver, bones, lungs, lymph nodes, or other organs. The key step is usually a biopsy of one of the accessible lesions.
A biopsy can provide a great deal of information even when we do not know where the cancer originated
The pathologist first examines the tissue under a microscope to determine what type of malignant cells are present. Most CUPs are carcinomas, and a common histological type is adenocarcinoma. Poorly differentiated carcinomas, squamous cell carcinomas, and other, less common tumor types may also be identified.
However, modern pathology goes far beyond simply examining cells under a microscope. Various immunohistochemical stains are used to detect proteins characteristic of specific types of tissue. Based on the combination of these markers, the pathologist can often make a reasonably accurate assessment of which organ the cancer may have originated from. For example, a particular immunohistochemical pattern may suggest that the tumor behaves like colorectal, kidney, lung, breast, or another type of cancer – even when the primary tumor itself cannot be found.
Therefore, the question in CUP today is not only: “Where is the primary tumor?” but also: “What is the biology of this tumor, and which known type of cancer does it most closely resemble?” This can be extremely important when choosing treatment.
What tests are performed?
The diagnostic work-up depends on the location of the metastases, symptoms, sex, histopathological findings, and other clinical information.
It most commonly includes a detailed clinical examination, laboratory tests, biopsy, and CT scans of the chest, abdomen, and pelvis. Depending on the findings, additional tests such as MRI, mammography, endoscopic examinations, or PET/CT may also be performed.
It is important to emphasize that the goal is not to perform every possible test. If the primary tumor has not been identified after an appropriate diagnostic work-up, further investigation is primarily justified when there is a realistic possibility that the result will change treatment.
Repeatedly performing additional tests simply to find the primary site at all costs is not necessarily beneficial for the patient.
Is PET/CT enough to find the primary tumor?
PET/CT can be a very useful examination and is generally recommended as part of the routine work-up for cancer of unknown primary, but it cannot always identify the site where the cancer originated. Some tumors are too small, some show relatively low uptake of the radiotracer, and increased uptake on PET/CT is not specific to cancer alone.
Therefore, PET/CT is not a “primary tumor detector” that will solve the problem of CUP in every patient. It is used selectively when there is a reasonable possibility that the findings will help determine the extent of the disease or change the treatment approach.
Not all CUPs are the same
This is a particularly important point. In the past, CUP was largely regarded as a single disease, and most patients were treated with similar, empirically selected chemotherapy. Today, we know that CUP includes several very different groups of cancers.
In some patients, the clinical presentation, pattern of metastatic spread, and characteristics of the cancer cells correspond so strongly to a particular type of cancer that the disease can be treated similarly to that known primary tumor. For example, there are CUP tumors with characteristics of colorectal cancer (colon-like CUP), kidney cancer (renal-like CUP), breast cancer, prostate cancer, ovarian cancer, lung cancer, and several other tumor types.
These subgroups are particularly important because they may have a different prognosis and, even more importantly, may be treated with therapies specific to the type of cancer they biologically resemble. This is why current ESMO guidelines classify CUP into different clinical and biological subgroups rather than treating all patients in the same way.
Can CUP be cured?
In most patients, CUP is diagnosed when the disease is already present in multiple parts of the body, which means that a complete cure is usually not possible. However, the same rule does not apply to everyone.
There are more favorable subgroups of CUP that may have a significantly better course and can be treated similarly to the corresponding known primary cancer. Of particular interest is oligometastatic disease, in which only one or a few limited metastatic lesions are present. Current ESMO guidelines also recognize this subgroup of CUP, in which local treatment with surgery and/or radiotherapy may have potentially curative intent in carefully selected patients.
Therefore, a diagnosis of CUP alone is not sufficient to determine prognosis. The extent of the disease, histological type, biological characteristics of the tumor, possibilities for targeted therapy, and the patient's general condition are all crucial factors.
How is cancer of unknown primary treated?
Treatment depends on the CUP subgroup. If the findings strongly correspond to a particular known type of cancer, treatment may follow the principles used for that cancer.
If the tumor's origin cannot be determined with sufficient confidence, empirical chemotherapy is traditionally used for advanced disease, often involving a platinum-based combination.
Radiotherapy can be very effective for controlling individual metastases, such as painful bone lesions or other local problems. Surgery may also be used in selected situations. However, the treatment of CUP has begun to change in recent years.
Molecular profiling: perhaps identifying the organ is no longer the most important goal
The development of modern molecular oncology is changing the way we think about CUP. Tumor tissue can be analyzed further using methods such as NGS (next-generation sequencing) to identify genetic alterations that drive tumor growth.
This raises an entirely different question. Instead of asking only: “Did this cancer originate in the lung, stomach, or another organ?” we can ask: “Does this tumor have a molecular alteration that we can target with a drug?”
In some patients, biomarkers can be identified that open the possibility of targeted therapy or immunotherapy. Molecular profiling is therefore becoming an increasingly important part of the modern approach to CUP.
However, identifying a mutation does not automatically mean that an effective treatment exists for it. Molecular testing results must always be interpreted in the context of the tumor type, available treatments, and the evidence that a particular therapy can genuinely benefit the patient.
Precision oncology is already changing the treatment of CUP
A good example is the international CUPISCO trial, in which extensive molecular profiling was performed in patients with unfavorable CUP. Patients whose treatment was selected according to the molecular characteristics identified in their tumors after initial therapy had longer progression-free survival than patients treated with standard chemotherapy.
This does not mean that chemotherapy has disappeared from the treatment of CUP, nor that a targeted therapy can be found for every patient. However, it demonstrates the direction in which oncology is evolving: from treating cancer solely according to the organ in which it originated toward treatment based on the biology of the tumor itself.
Should we always continue searching for the primary tumor?
No. This is perhaps one of the most important messages of this article. It is completely understandable that patients may find it difficult to accept that doctors know they have cancer but cannot say where it originated. This can create the feeling that the diagnostic work-up is somehow “incomplete.”
However, at a certain point, a more important question becomes: Will an additional test change what we do? If the answer is no, continuing to search for the primary tumor may simply delay the start of treatment without providing any real benefit. On the other hand, if identifying, or at least reliably determining, the tumor's origin would allow for a completely different treatment approach, then further diagnostic testing clearly makes sense.
CUP is no longer simply “cancer of unknown origin”
Cancer of unknown primary remains one of the more complex situations in oncology. However, the way we understand it has changed significantly. Today, we do not simply try to find a hidden primary tumor. Pathology, immunohistochemistry, and molecular diagnostics allow us to determine with increasing precision what kind of tumor we are dealing with, even when we cannot say with certainty where it originated.
And this information may ultimately be more important than the name of the organ itself. In modern oncology, the goal is therefore becoming less about finding the primary site at all costs and increasingly about finding the best possible treatment for the individual patient and their specific tumor.
Diagnosis and treatment of CUP by the Onkologija.net team
An individualized approach is particularly important in cancer of unknown primary. It is not enough simply to establish that the primary site has not been identified – the location and pattern of metastatic spread, histopathological and immunohistochemical findings, and, when indicated, the molecular characteristics of the tumor all need to be considered together.
At Onkologija.net / Poliklinika Anova, we can provide patients with CUP with a comprehensive oncological assessment of their previous diagnostic work-up and treatment options, including an assessment of the need for additional histopathological analysis and molecular tumor profiling.
NGS (next-generation sequencing) can play a particularly important role. This is comprehensive molecular testing that simultaneously analyzes numerous genes in tumor tissue to identify alterations that may be relevant when selecting treatment.
At Poliklinika Anova, we provide NGS tumor testing followed by oncological interpretation of the results. A list of identified mutations alone is not enough: it is necessary to determine which alterations are truly relevant, whether an appropriate targeted therapy or immunotherapy exists, and how strong the available evidence is for its effectiveness in that particular tumor.
This is particularly important in CUP because, in some patients, the molecular profile of the tumor may reveal treatment options that do not depend solely on whether we have successfully identified the organ in which the cancer originated. More information about genomic profiling (NGS) is available here.
Depending on the findings and previous treatment, systemic anticancer therapy can also be administered at Poliklinika Anova, including chemotherapy, targeted therapy, and immunotherapy when appropriately indicated.
The goal of this approach is not to give the primary site a name at all costs, but to obtain information with genuine therapeutic value and use it to select the best available treatment option for each individual patient.
