Cancer of Unknown Primary (CUP)

Cancers of unknown primary (CUP), also known as cancers of occult primary, are a type of cancer that has spread from an unknown point of origin. It is known as a secondary or metastatic cancer (cancer that has spread from another part of the body), and the primary cancer it originated from cannot be located. As it is a secondary or metastatic cancer, patients with CUP often present at an advanced stage of disease.

There are many reasons that a primary cancer can’t be located, such as the primary cancer is too small to be detected, the immune system has already killed the primary cancer, the primary cancer may have been removed during surgery for another condition, or the primary cancer is hidden by a larger secondary cancer nearby. While it is helpful to know where the primary cancer is located, the doctors can perform tests on the secondary cancer to determine what it most likely is, and how to treat it.

CUP is generally found equally among the sexes, and is most likely to be found in people over 60 years old. However, anyone can develop this disease.

Types of CUP

Although the primary cancer cannot be located, doctors can perform tests on the secondary cancer to determine the type of cells the cancer originated from. In most cases of CUP, the patient has a type of carcinoma (cancer arising from epithelial cells and tissues that line organs). There are many different types of carcinomas, which are categorised by the type of epithelial cell they develop from.

Adenocarcinoma

Adenocarcinomas are cancers that arise from mucus-producing glands in organs, and is the most common type of cancer cell found in patients with CUP. They generally have primary cancers originating in the lungs, liver, stomach, pancreas, bowel, and/or prostate, but could potentially start in other parts of the body as well.

Poorly Differentiated Carcinoma

Poorly differentiated carcinomas are cancer cells that have enough detail for a doctor to determine that they are a carcinoma by examining them under the microscope, but they cannot determine what type of carcinoma the cancer is. They are the second most common type of cancer cell found in patients with CUP, and generally don’t provide enough information to suggest where the primary cancer is located.

Squamous Cell Carcinoma (SCC)

Squamous cell carcinomas (SCCs) are cancers that arise from squamous cells, which form the surface layer of the skin and the lining of hollow organs, the respiratory tract, and the digestive tract. They generally have primary cancers originating in the head and neck area, oesophagus, lungs, pancreas, cervix, vagina, or skin, but could potentially start in other parts of the body as well.

Rare types of CUP

These types of CUP are considered rare:

Neuroendocrine tumours (a type of malignancy that often produce hormones and may be located in the gastrointestinal tract or pancreas).
Undifferentiated neoplasms (cells that can be determined as a cancer, but cannot determine what type of cancer they are).
Metastatic neck cancer with occult primary.

Treatment

When cancers are detected, they are staged and graded based on size, metastasis (whether the cancer has spread to other parts of the body) and how the cancer cells look under the microscope. Staging and grading helps your doctors determine the best treatment for you. However, as CUP is a disease with an unknown primary cancer, there is currently no standard staging and grading system for this disease. Instead of staging and grading, your doctor will recommend a treatment plan based on the following factors:  

Your age. 
General health. 
The location of the secondary cancer.
Where the primary cancer is suspected to be located.
Diagnostic test results.
What will give you the best outcome.
Your treatment preferences.

Your doctor may also recommend genetic testing, which analyses your tumour DNA and can help determine which treatment has the greatest chance of success. They will then discuss the most appropriate treatment option for you.  

Treatment for CUP may include:

Chemotherapy.
Hormone therapy.
Targeted therapy.
Immunotherapy.
Radiation therapy.
Surgery (generally to remove as much of the cancer as possible).
Clinical trials.
Palliative care.

For more information on the treatment options, please refer to the Rare Cancers Australia treatment options page.

Risk factors

Each case of CUP will have different risk factors, depending on the type of primary and secondary cancer you have. As each different cancer has a different set of risk factors, it is difficult to determine definitive risk factors of CUP.

Generic factors that may increase the risk of developing cancer may include:

Older age.
Having an unhealthy diet.
Having a history of drinking.
Having a history of smoking.
Family history.
Being overweight.
Having certain infections.
Not getting enough exercise.

Not everyone with these risk factors will develop the disease, and some people who have the disease may have none of these risk factors. See your general practitioner (GP) if you are concerned.

Early symptoms

Each case of CUP will have different symptoms, depending on the type of primary and secondary cancer you have. As each different cancer has a different set of symptoms, it is difficult to determine definitive symptoms of CUP.

Generic symptoms that may be indicative of cancer include:

Fatigue.
Unexplained weight loss/loss of appetite.
Nausea and/or vomiting.
Shortness of breath.
Discomfort in the chest area.
Persistent cough.
Pain in the bones, back, head, abdomen, or other areas.
Swelling or bloating of the abdomen.
Changes in bowel habits, potentially including:
- Constipation.
- Diarrhoea.
Jaundice (yellowing of the skin and/or eyes).
Swollen lymph nodes in the neck, underarm, chest, and/or groin.

Not everyone with the symptoms above will have cancer, but see your GP if you are concerned.

Diagnosis/diagnosing

If your doctor suspects you have CUP, they may order the following tests to confirm the diagnosis and refer you to a specialist for treatment.

Physical examination

Your doctor will collect your overall medical history, as well as your current symptoms. Following this, they will examine your body) to check for any abnormalities.

Blood & Urine tests

Blood and urine tests are used to assess overall health and detect any abnormalities. Some of these tests may include:

General blood test to assess overall health.
Full blood count, which measure the levels of red blood cells, white blood cells and platelets.
Blood chemistry and/or blood hormone studies, which analyse the levels of certain hormones and other substances in the blood.
Blood tests to examine tumour markers (chemicals released by tumour cells). Common tumour markers that may be indicative of cancer include:
- Prostate specific antigen (PSA) (may indicate prostate cancer).
- Alpha-fetoprotein (AFP) (may indicate testicular or liver cancers).
- Human chorionic gonadotrophin (HCG) (may indicate testicular or ovarian cancers).
- Carcinoembryonic antigen (CEA) (may indicate bowel, lung, pancreatic, stomach, ovarian, breast, thyroid or liver cancers).
- Cancer antigen 125 (CA125) (may indicate ovarian, endometrial, fallopian tube or peritoneal cancers).
- Cancer antigen 19-9 (CA19-9) (may indicate pancreatic, stomach, bile duct, gallbladder or ovarian cancers).
- Caner antigen 15-3 (CA15-3) (may indicate breast cancer).
Urinalysis, which analyses the colour of your urine and its contents (e.g., sugar, protein, red and/or white blood cells etc.). 
Urine cytology (collection of urine samples over a three-day period for analysis).

Imaging tests

The doctor will take images of your body using magnetic resonance imaging (MRI), a computed tomography scan (CT scan), mammogram, tomosynthesis/DBT, and/or positron emission tomography (PET scan), depending on where it is suspected the cancer is. The doctor may also look at other parts of the body and looks for signs of metastasis.

If the doctor finds metastasis without finding the primary cancer, you will be diagnosed with CUP.

Endoscopy

An endoscopy is a surgical procedure that involves inserting a long, flexible tube with a light and small camera into the body. You will be given a sedative or anaesthetic throughout the procedure, and will be asked to fast for several hours prior to the procedure. An endoscopy is often done as a day surgery. Your doctor will discuss the risks and any possible complications prior to the procedure.

Throughout the procedure, your doctor may also perform an endoscopic ultrasound to guide the needle during a biopsy, or to check for signs of cancer metastasis.

There are several types of endoscopy that you may have depending on where it is suspected the cancer is. This may potentially include:

Bronchoscopy (tube inserted through mouth or nose to examine the trachea, lungs and/or respiratory tract).
Colonoscopy (tube inserted through the anus to examine the large bowel).
Colposcopy (doctor uses a speculum to separate the walls of the vagina, and apply a vinegar-like liquid and iodine to the cervix and vagina to help highlight any abnormal areas).
Cystoscopy (tube inserted through urethra to examine the bladder).
Gastroscopy (tube inserted through mouth to examine stomach and part of the small bowel).
Hysteroscopy (tube inserted through vagina to examine the uterus).
Laparoscopy (tube inserted through incisions in the abdomen to examine the stomach, liver, and/or uterus).
Laryngoscopy/microlaryngoscopy (tube inserted through the mouth to examine the larynx (voice box)).
Mediastinoscopy (tube inserted through small incisions in the neck to examine the mediastinum (space between the lungs)).
Nasoendoscopy (tube inserted through the nose to examine the lining of the nasal passages and nasopharynx).
Oesophagoscopy (tube inserted through the mouth or nose to examine the oesophagus).
Proctoscopy (tube inserted through the anus to examine the rectum and anus).
Sigmoidoscopy (tube inserted through the anus to examine the rectum and lower portion of the colon).
Thoracoscopy (tube inserted through small incisions in the chest to examine the lungs).
Ureteroscopy (tube inserted through the urethra to examine the urethra, renal pelvis, bladder, and ureters).

Biopsy

A biopsy is a procedure that is undertaken to remove a sample of tissue or cells from the body to be tested in a laboratory to detect any abnormalities. The tissue sample will then be analysed for cancer cells. This can be done by a fine needle aspiration (FNA), a core needle biopsy (CNB), a vacuum-assisted core biopsy, or a surgical biopsy.

Prognosis (Certain factors affect the prognosis and treatment options)

While it is not possible to predict the exact course of the disease, your doctor may be able to give you a general idea based on the rate and depth of tumour growth, susceptibility to treatment, age, overall fitness, and medical history. Generally, CUP is diagnosed at a late stage of disease, and has already spread to different areas of the body, and may not have as good of a prognosis as other types of cancer. It is very important to discuss your individual circumstances with your doctor to better understand your prognosis.  

References

^{Some references are to overseas websites. There may be references to drugs and clinical trials that are not available here in Australia.}