CUP syndrome (cancer of unknown primary)

CUP syndrome is an unusual form of cancer where doctors detect secondary tumors around the body, so-called metastases. However they do not find the tumor of origin. This why it’s called CUP or cancer of unknown primary.

At a glance

  • In CUP syndrome metastases are found in the body but the primary tumor is not.
  • This is an advanced form of cancer where the cancer has already spread (“metastasized”).
  • The causes and risk factors for CUP syndrome are largely unknown.
  • The symptoms and progression depend on where the cancer cells originated and where they have metastasized to.
  • One diagnostic approach involves histological examinations of tissue to identify the primary tumor.
  • In most cases, CUP syndrome cannot be cured; treatment is on an individual basis and is aimed at alleviating symptoms and maintaining quality of life.

Note: The information in this article cannot and should not replace a medical consultation and must not be used for self-diagnosis or treatment.

CUP syndrome (cancer with unknown primary origin): patient lying in front of an MRI tube. A doctor is standing behind a glass screen and observing the patient in the background.

What is CUP syndrome?

In “normal” tumors the cancer originates in a specific organ and then spreads or “metastasizes” to other parts of the body. CUP syndrome is an unusual form of cancer where doctors detect secondary tumors around the body, so-called metastases. However they do not find the tumor of origin. This why it’s called CUP or cancer of unknown primary.

Almost any type of tumor can be implicated in CUP syndrome. Cancer cells have detached themselves from an unknown tumor of origin and migrated to other tissues or organs, so CUP syndrome is an advanced form of cancer that can grow aggressively.

Many tumors form metastases in the liver, lung, bones or lymph nodes in particular. But growths can also occur in the brain or the skin. In patients with CUP syndrome metastases also migrate to sites in the body where tumors would not usually spread otherwise. Metastases can occasionally occur simultaneously in several different organs. 

Where does the cancer originate?

In patients with CUP syndrome, doctors search for the “primary tumor”, the tumor where the cancer originated. If they find the tumor of origin the cancer is assigned to the specific organ or tissue. If the search is unsuccessful the diagnosis of CUP syndrome is retained.

What are the symptoms of CUP syndrome?

The symptoms of CUP syndrome, like its potential origins, vary widely from patient to patient.  

The specific symptoms will depend in particular on the organ or tissue to which the metastases migrate. 

So there are no typical symptoms of CUP syndrome. However, in most cases they will be symptoms of any advanced cancer such as: 

  • swollen lymph nodes that are firm to the touch, do not move and are not painful
  • enlarged abdominal girth, swelling or hard masses in the chest or abdomen
  • unusual shortness of breath (dyspnea) or pain in the chest or abdomen 
  • pain in the bones
  • persistent fatigue, exhaustion or loss of appetite
  • involuntary weight loss

Anyone with these symptoms should consult a doctor. This is particularly important if they are not caused by an infection and last longer than a few days or even weeks. 

What causes CUP syndrome?

The causes of CUP syndrome are still largely unknown. It is known that the metastases in the body must have come from an original cancer site.  

Cancers are based on genetic mutations that convert normal cells in the body into malignant cancer cells. These cancer cells start to grow uncontrollably into surrounding tissue, destroying it. Cancer cells are also capable of detaching themselves from the primary site, spreading around the body through the lymph system or bloodstream and migrating into other organs to form metastases. 

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But why is it that the metastases can be detected but not the tumor of origin? Experts believe that some of the cancer cells’ properties act in favor of CUP syndrome. They have two different models to explain this:

  • One theory is that the metastases in CUP syndrome migrate very quickly after the original cancer occurs without actually forming any primary tumor at all. Or the primary tumor is so small that it does not cause any symptoms and goes undetected by the usual tests.
  • Another theory is that the body’s immune system has managed to deal with the tumor of origin but not with the metastases that form in the meantime.

How common is CUP syndrome?

The medical literature has a number of different estimates of the prevalence of CUP syndrome. Around 2 to 5 out of 100 cancers are CUP syndromes. Around half of those affected are under 60 and around the same numbers of men and women get CUP syndrome. 

Around 2 to 5 out of 100 newly diagnosed cancers are CUP syndromes.

The number of CUP diagnoses has declined in recent years. This may be because the tumor of origin is actually being detected in an increasing number of cases, or doctors have at least been able to clarify the tissue from which the cancer cells have originated. In these cases the diagnosis of CUP syndrome changes to the relevant type of cancer.

How does CUP syndrome progress?

Like its symptoms, the progression of CUP can vary significantly from one patient to another. It depends on where the cancer cells originally came from and the tissue to which they have migrated. So no overall prognosis can be provided. However a cure is relatively unlikely for most patients with CUP since the cancer advances rapidly in most cases.  

The prognosis is better for around one in five patients. In these cases the biological properties of the cancer cells suggest a specific tumor of origin. Doctors can then introduce appropriate treatment. These patients will generally have a prognosis that is similar to that of cancer patients at the same stage with a known primary tumor. 

How is CUP syndrome diagnosed?

Where doctors detect cancer cells expressed as metastases in a patient they focus initially on determining how many metastases there are and where precisely they are situated.  

They also try to identify the tumor of origin. For patients this often means that testing can drag out over several weeks, requiring a great deal of patience and endurance.  

The doctors start by asking patients about their overall health status (medical history). This is followed by a thorough physical examination. However, scans are the main diagnostic tool. These mostly involve a computed tomography (CT) scan of the chest, abdomen and pelvic cavity. But they may also include: 

  • positron emission tomography (PET) scan
  • magnetic resonance imaging (MRI) scan
  • endoscopy of various organ systems suggested by symptoms
  • ultrasound breast scan and mammography
  • transvaginal ultrasound in women
  • nuclear medicine scan (scintigraphy) 
  • determination of endogenous (from your own body) substances in the blood indicating cancer (tumor markers)
CUP syndrome is diagnosed by taking a medical history, a physical examination or scan.

However the search for the tumor of origin does not continue for ever. The key diagnostic goal is to exclude cancers such as lymphomas or germ cell tumors. These may present a clinical picture similar to CUP syndrome but generally respond well to chemotherapy and are potentially curable. 

Doctors also try to identify whether the tumor of origin could be a sex-specific form of cancer such as prostate cancer or breast cancer.  

However the doctors may never identify the tumor of origin even after rigorous testing and scans. If that is the case they use histological examinations of tissue to try to identify the origin of the cancer cells.  

Histological examinations 

Histological examinations of the metastasized CUP tissue are particularly important. Tissue samples are treated with a special stain and examined under the microscope. They are also subjected to molecular biology and genetic testing. This involves searching for typical characteristics of specific cancers.  

The examinations are intended to help determine:  

  • whether the cells can be assigned to a specific organ of origin such as the prostate, lung, breast or bowel.
  • the main type of cancer involved – carcinoma, melanoma, sarcoma or lymphoma. 
  • the sub-type of cancer involved – for example, adenocarcinoma, squamous cell carcinoma (SCC) or neuroendocrine cell carcinoma (NEC).

So the diagnostic goal is to identify the characteristics of the cancer that are most important for treatment planning purposes.

How is CUP syndrome treated?

Most patients with CUP syndrome receive palliative treatment. Curative treatment is only possible in rare cases. The overall goal of treatment is to slow the growth of the metastases, alleviate symptoms and maintain quality of life as best as possible. Generally, treatment should be personalized and take the following into account: 

  • overall health  
  • likely progression of the disease
  • patient’s individual requests

The crucial factor in the treatment of cancer of unknown primary is whether the organ of origin can be determined from examination of the cancer cells. Treatment can be targeted far more precisely if the features of the tumor can be precisely assigned to a specific suspected origin.

So treatment varies depending on whether the primary tumor:

  • is located. If so, it is by definition no longer a CUP syndrome. The cancer is instead assigned to the relevant organ or tissue. In most cases, prognosis is more favorable. Patients are treated in accordance with the treatment guidelines for the specific type of cancer. Their treatment usually follows the recommendations for patients with the advanced, metastasized form of the cancer.
  • is suspected. Here too, patients often have a better prognosis and are also treated in accordance with the treatment guidelines for the specific type of cancer.
  • cannot be identified. In most cases, metastases have already spread to the internal organs. So the prognosis is worse. However treatment is still an option; in most cases this will be palliative, mostly involving chemotherapies with the minimum of adverse side effects that cause least discomfort to patients. 

But it’s not just the origin of the tumor that is important here. Another important factor is the extent to which the CUP syndrome metastases have already spread. Are they just located at a single site, or have they already infected several organs?  

Localized metastases

Doctors can remove localized metastases by surgery or targeted radiotherapy, sometimes using a combination of the two. However surgery is only appropriate if there is a chance of curing the cancer or alleviating symptoms. Targeted radiotherapy is designed to reduce the size of metastases and prevent them from growing, and in the case of bone metastases to alleviate pain. 

Systemic therapies

However, since most CUP syndromes have already metastasized into multiple organs, treatments that act on the whole body (“systemic therapies”) are more important for many people with CUP syndrome. For most of these patients, chemotherapies with low adverse side effects are the treatment of choice.   

Targeted drugs are also suitable for systemic treatment as they block biological mechanisms that are important for cancer growth but not for healthy tissue. However these drugs are only available for patients with tumor tissue that exhibits specific biological properties. Therapy is ineffective on other types of tissue. 

What are the procedures for chemotherapy and targeted therapies and what side effects do they have? You can find detailed information on the different treatments on the German Cancer Research Center’s Cancer Information Service website (in German).

What happens after CUP syndrome treatment?

Cancer treatment can be physically and mentally exhausting. Medical rehabilitation (rehab) after cancer therapy aims to help patients regain their strength. It is also designed to help them cope with the consequences of the disease and its treatment as best as possible.  

A medical rehab program is based on the individual patient’s medical history and the restrictions in place. Psycho-oncological counseling can help people with CUP syndrome when worries and fears become overwhelming.  


Whether CUP patients require aftercare will depend on the specifics of the disease. If the aim of the treatment was to effect a cure, the CUP patient should receive intensive aftercare. However this is rarely the case.  

The cancer can’t be cured? If so, check-ups and regular ancillary care can help to identify and alleviate distressing symptoms. The aim is to maintain the patient’s quality of life for as long as possible. 

What changes following a CUP syndrome diagnosis?

Suddenly facing a diagnosis of cancer is extremely distressing for most people. This applies particularly if the disease is already at an advanced stage. The nature of CUP syndrome itself also exacerbates the situation: despite numerous examinations and diagnostic tests, doctors may never be able to identify the origin of the cancer. 

What’s more, the disease develops very rapidly in many people, leaving very little time for them to adjust to the new situation. They have to weigh up the risks and benefits of treatment options over and over with their doctors. Patients with CUP syndrome usually require intensive care and monitoring.  

But that doesn’t mean patients have to spend the whole time hospitalized or regularly go to hospital for treatment in an ambulance: many treatments or checkups can be provided by specialists in medical practices or specialist outpatient clinics.  

Frequent contact with medical staff is also important as metastasized cancers can lead to conditions that can change very rapidly. The regular checkups are a chance to discuss pain, nausea, dietary or weight problems as well as any other distressing symptoms. There is usually something that can be done to help with these problems.

Who are the best contacts for people with CUP syndrome?

There is no official list in Germany of clinics that treat patients with CUP syndrome. Certified organ centers exist for other types of cancer but not for CUP syndrome. The patients’ individual situations will determine how they are treated. An interdisciplinary approach is often required for both diagnosis and treatment of patients with CUP.

University hospitals or other large clinics generally have specialist departments that work together on an interdisciplinary basis. Some of the large cancer centers also provide dedicated clinics for patients with CUP syndrome as part of their interdisciplinary outpatient cancer service.

You can find information on how to find the right clinic on the German Cancer Research Center’s Cancer Information Service website (in German).

Or you can contact professional associations to identify specialist centers. One of these in Germany is the CUP Syndrome sub-group of the Working Group on Internal Oncology (AIO).  

Do you have further questions about dealing with the condition in everyday life and additional support options? You can find information about this on the German Cancer Research Center’s Cancer Information Service website (in German).

If you have any questions about CUP syndrome you can also make personal contact with the Cancer Information Service by dialing the freephone number 0800 - 420 30 40 or writing an email to 


In cooperation with the Cancer Information Service of the German Cancer Research Center (Krebsinformationsdienst des Deutschen Krebsforschungszentrums).

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