Carcinoma of Unknown Primary

Carcinoma of Unknown Primary

Cancer cells have a tendency to spread to nearby and distant organs from their site of origin. This phenomenon is called metastasis. Primary cancer denotes the first formed cancer in an organ or tissue. When these cancer cells spread to another organ and starts forming cancerous growths then they are called secondary cancer. Metastasis occurs at an advanced stage of the cancer. If liver cells become cancerous and spread to lungs then those cancer cells in the lungs resemble liver cancer cells and not lung cancer cells. Histological studies and several other tests help to understand the origin of cancer. However, in some cases it becomes very difficult to determine the origin of cancer. This type of cancer which has spread to different tissues and organs, but whose origin remains unknown is called cancer of unknown primary. It is very important to try to find out the primary cancer since the treatment varies with the type of primary cancer. Therefore, it is very difficult to treat a patient with cancer of unknown primary.

Causes for failure in detecting the primary cancer

  • Very small cancerous growth at the site of origin is difficult to detect with the help of imaging studies and other tests
  • Immune system acted efficiently to get rid of the primary cancer cells, which are less aggressive.
  • Removal of an infected or diseased part, which unknowingly was the site of primary cancer.

Causes of CUP

The cause remains unknown since the primary cancer could not be detected.


Carcinoma of unknown primary (CUP) is one of the 10 most frequent cancers worldwide. It constitutes 3-5% of all human malignancies. According to the American Cancer Society, 30,680 cases of cancer of unknown primary site were diagnosed in the US, representing 2% of all cancer cases. Black people may be more prone to develop this disease in comparison to white, Hispanic, and Native American people. CUP is diagnosed between the ages of 60 and 79 years in most cases. There is no significant difference in incidences between male and female, although some old data suggests male predominance.

Types of CUP

Depending on its histological characteristics, CUP can be classified as:

1) Adenocarcinoma (60%),

2) Poorly differentiated carcinoma (20–30%),

3) Squamous cell carcinoma (5–8%)

4) Undifferentiated malignant neoplasm (2–3%)

5.) Neuroendocrine carcinoma

6.) Miscellaneous others


CUP patients more likely to respond to therapy:

1) Women with adenocarcinoma involving axillary lymph nodes

2) Peritoneal carcinomatosis in women

3) Cervical or inguinal lymph node metastases from squamous cell carcinoma

4) Middle-line CUPs

5) Poorly differentiated neuroendocrine carcinoma

6) Men with blastic bone metastases and elevated PSA (adenocarcinoma)

7) Patients with a single, small, potentially resectable tumor

8) Those under 50 years of age


Unfortunately, the majority of CUP (approximately 85%) patients do not fit into any of these categories and their prognosis is much more difficult to predict. The unfavorable subsets are:

1) Adenocarcinoma metastatic to the liver or other organs

2) Non-papillary malignant ascites (adenocarcinoma)

3) Multiple cerebral metastases (adeno or squamous carcinoma)

4) Multiple lung/pleural metastases (adenocarcinoma)

5) Multiple metastatic bone disease (adenocarcinoma)

Signs and Symptoms of CUP

  • The symptoms of CUP depend on the organs affected. Sometimes no symptoms are detected. Symptoms that may be found are:
  • Swelling of lymph nodes that are not painful. This condition is called lymphadenopathy, which may be due to spreading of cancer to lymph nodes.
  • Cancer that has spread to liver or spleen may lead to formation of a mass in the abdominal region and accumulation of fluid in the abdomen.
  • Cancer that has spread to lungs can cause difficulties in breathing.
  • Long lasting pain due to large-sized tumors.
  • Spreading of cancer to bones may cause severe bone pain
  • Lumps or tumors on skin can develop on skin because of spreading of cancer to skin.
  • Other general symptoms may include persistent fever, cough, unusual bleeding, change in bowel habits, night sweats, weight loss, loss of appetite and fatigue.
  • Excessive production of hormones in some forms of cancers may cause other symptoms related to metabolism.


Physical exam and history: The patient is physically examined to check if there are any lumps or other symptoms related to cancer. Past illness or habits of the patient can give an idea regarding the disease.

Routine testing of the urine: The urine should be analyzed routinely to detect abnormal presence of blood, sugar, protein, etc.

Blood chemistry tests: The presence of certain substances in excess can be indicative of cancer.

Complete blood count: The number of erythrocytes, leucocytes and platelets are counted and the amount of hemoglobin in the red blood cells is measured.

Chest x-ray: It is an imaging technique with x-ray to get pictures of organs inside the chest.

Fecal occult blood test: In this procedure, blood can be detected in the stool of patients. It can be indicative of some form of cancer.

A biopsy is the process of viewing cells and tissues under a microscope that are removed from the affected site. Cancer cells have certain characteristic features that can be viewed under a microscope in a laboratory. Biopsies can be of many different types. These are Excisional biopsy, Incisional biopsy, Core biopsy and Fine-needle aspiration (FNA) biopsy

Histological study: Slides with thin sections of the tissues are stained and viewed under a microscope to look for changes in the cells related with cancer.

Immunohistochemistry study: Specific antibodies are used to check the expression of specific proteins in the cells, which may indicate the specific type of cancer. It is of great importance since it can help to find out the type of primary cancer.

Reverse transcription–polymerase chain reaction: Expression of specific genes is checked in the tissue or cells obtained from the patient.

Cytogenetic analysis: Alterations in chromosomes are studied under a microscope in the cells of a tissue, which are obtained from the patient. This helps in predicting the type of primary cancer.

Light and electron microscopy: Cells are analyzed under high-powered microscopes to check for signs of cancer.

CT scan: The CT scan is a procedure by which images of the internal organs of the body can be obtained with a help of x-rays. A contrasting dye is injected in the veins so that the images are clearly understood. The images can be viewed with the help of a computer.

MRI scan: This imaging procedure is based on the use of radiowaves in the presence of a magnet. The images produced can be viewed with the help of a computer attached to the machine.

PET scan: The PET scanner is an imaging technique, which helps to find out the spread of the disease.

Mammogram: This refers to a kind of x-ray of the breast.

Endoscopy: Endoscopy is the most sensitive diagnostic method for detecting gastric cancer. When combined with endoscopy and radiologic modalities, endoscopic ultrasound (EUS) can provide more information about depth of tumor invasion.

Tumor marker test: Certain substances are found in the blood, urine and tissues in increased amount when a person is having cancer. These substances are known as tumor markers. The blood may be checked for the levels of alpha-fetoprotein (AFP), beta human chorionic gonadotropin (β-hCG), or prostate-specific antigen (PSA).

Thyroid scan: Examination of thyroid is done to check whether cancer has originated in thyroid or not.


Staging of any cancer is based on the extent of metastasis of the cancer from the primary site. Prognosis is best for Stage I cancer and worst for Stage IV cancer. A cancer is considered CUP only when it has spread beyond the site of origin and the primary site could not be detected. Therefore, CUPs cannot be staged correctly since the type of cancer is not determined and all of them are generally considered a stage IV cancer.


Several factors are considered when determining which treatment to use for CUP. In general, treatment may be of the following kinds:

Surgery: Surgery is used to treat CUP only if the cancer is found only in the lymph nodes or in one organ. A surgeon may remove the cancer as well as some of the healthy tissue around it.

Radiation therapy: High-energy rays are used to kill cancer cells and reduce the size of tumors. This can be done in two ways:

External radiation therapy: Radiation is given at the affected region by a machine from outside the body.

Internal radiation therapy: Radioactive substance sealed in a needle or wire is placed near the affected region. Radiation emitted from this radioactive substance kills the cancer cells.

The most common radiation treatment for CUP is external radiation therapy. The patient is normally treated five days a week for several weeks. Radiation can also be given for relieving pain and other symptoms when cancer has spread extensively.

Chemotherapy: Chemotherapy is the use of anticancer drugs to treat cancer. Adenocarcinomas or poorly differentiated CUPs are mostly treated with a combination of paclitaxel and cisplatin, or similar drug combinations, gemcitabine, and others. Squamous cell CUP may be treated with  5-fluorouracil (5-FU), cisplatin and a taxane,

It is useful for treating cancers that have spread extensively. Local treatments like radiation therapy or surgery may not help in such cases.

Hormone therapy: Hormone therapy is done to treat some cancers, which grow well in presence of specific hormones like estrogen. Drugs like tamoxifen and the aromatase inhibitors (anastrozole, letrozole, and exemestane) are used to lower the level of estrogen. Similarly, LHRH agonists such as leuprolide and goserelin, and anti-androgens such as flutamide and bicalutamide can be used to lower testosterone levels to treat CUP that has testosterone receptors.

Targeted therapy: Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. Epidermal growth factor receptors of cancerous squamous cells can be blocked by drugs like cetuximab to prevent the growth of these cancer cells.

Other Drugs:

Bisphosphonates are used to strengthen bones is cancer has spread to bones. Octreotide, which is related to a natural hormone, somatostatin can be used to treat some patients with neuroendocrine tumors.


Certain factors affect prognosis of CUP. These are the following:

1) Primary site of cancer and where has it spread.

2) Appearance of cancer cells under a microscope.

3) A case of recurrence or the patient had no previous history of cancer

4) Male or female

Prognosis is generally poor in most cases. Most CUPs cannot be treated, but some may respond to proper treatment. These subgroups respond better to treatment and are categorized before. Although many cancers of unknown primary cannot be cured, treatment may help the patient to live longer or improve the quality of life.

The survival rate is around three to four months with less than a 25% survival rate one year after diagnosis, and a 10% survival rate after five years. When cancer of unknown primary has spread to multiple internal organs, the five-year survival rate after diagnosis is at approximately 5%. CUPs mostly spread fast and by the time the disease is diagnosed cancer has already spread to some extent.


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  3. This article was originally published on September 3, 2012 and last revision and update was 9/4/2015.