Unknown PrimaryLast Updated: December 02, 2010 This section has been reviewed and approved by the Cancer.Net Editorial Board, 10/10 Overview
Cancer begins when normal cells begin to change and grow uncontrollably, forming a mass called a tumor. A tumor can be benign (noncancerous) or malignant (cancerous, meaning it can spread to other parts of the body). Cancer is a group of more than 100 different diseases. In most people with cancer, it is easy for doctors to find the primary site (where the cancer began), and any secondary or metastatic site (if the cancer has spread). No matter where the cancer spreads, it is still named by the primary site. For example, breast cancer that has spread to the brain is called metastatic breast cancer, not brain cancer. For less than 5% of people diagnosed with cancer, the cancer is found at a secondary site but routine testing cannot help doctors find where the cancer began, called the primary site. These cancers are called carcinoma of unknown primary site or cancer of unknown primary (CUP). For some people, specialized testing can find the primary site; however, sometimes it cannot. This may be because the primary tumor is still very small, the body caused the primary tumor to shrink or disappear, and/or the primary tumor was removed during previous surgery for another condition, such as the removal of a mole on the skin or a hysterectomy (surgery to remove a woman’s uterus). Find out more about basic cancer terms used in this section. Statistics
CUP accounts for approximately 2% of cancers diagnosed in the United States each year. People with CUP are a diverse group, and prognosis (chance of recovery) varies widely. Often, treatments are limited for people whose cancer is widespread at the time of diagnosis. However, others have a cancer that can be successfully treated. These differences and survival rates are discussed in the Treatment section. Cancer survival statistics should be interpreted with caution. Estimates are based on data from thousands of cases of this type of cancer in the United States each year, but the actual risk for a particular individual may differ. It is not possible to tell a person how long he or she will live with CUP. Learn more about understanding statistics. Statistics adapted from the American Cancer Society. Risk Factors
A risk factor is anything that increases a person’s chance of developing cancer. Although risk factors can influence the development of cancer, most do not directly cause cancer. Some people with several risk factors never develop cancer, while others with no known risk factors do. However, knowing your risk factors and communicating them to your doctor may help you make more informed lifestyle and health care choices. Since CUP can be almost any type of primary cancer, the risk factors for all types of cancer are can be risk factors for CUP. The following factors can raise a person’s risk of developing CUP:
Symptoms
Since CUP can appear anywhere in the body, the initial symptoms can vary. Usually, symptoms are related to the area where the cancer is found, most commonly the liver, lungs, bones, and lymph nodes. People with CUP may experience the following symptoms or signs. Sometimes, people with CUP do not show any of these symptoms. Or, these symptoms may be caused by a medical condition that is not cancer. If you are concerned about a symptom or sign on this list, please talk with your doctor.
Even when the primary site cannot be found, a patient’s signs and symptoms can often help the doctor plan effective treatment. Careful evaluation and testing of the tumor tissue removed during the biopsy (see Diagnosis) can sometimes give clues about where the tumor began. Also, finding where the cancer has spread can help decide which treatments are most appropriate. Diagnosis
By definition, CUP is found after it has spread from where it started. Doctors use many tests to try to find the primary site. Some tests may also determine which treatments may be the most effective. For most types of cancer, a biopsy is the only way to make a definitive diagnosis of cancer. Imaging tests will likely be used to look for other areas where the cancer has spread. A biopsy is the removal of a small amount of tissue for examination under a microscope. Other tests can suggest that cancer is present, but only a biopsy can make a definite diagnosis. The sample removed during the biopsy is analyzed by a pathologist (a doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease; see below). The type of biopsy performed will depend on the location of the cancer. Learn more about what to expect when having a biopsy. Evaluation by a pathologist A pathologist diagnoses cancer by looking at the sample of the tumor from the biopsy. The results of the initial biopsy gives important information and helps doctors plan additional testing. Most people with CUP have one of these four different types of tumors: Adenocarcinoma. Nearly 60% of people with CUP have adenocarcinoma. Adenocarcinoma can begin in the glandular tissue of most internal organs (for example, lung, stomach, pancreas, colon, ovary, and breast). Because of this, when adenocarcinoma is found in a metastatic site, it is extremely difficult for the pathologist to tell where it began. Poorly differentiated carcinoma. Nearly 20% to 30% of people with CUP have poorly differentiated carcinomas. These cancers need extra tests by the pathologist, since some very treatable cancers may initially be diagnosed as poorly differentiated carcinoma. If testing finds that the cancer is lymphoma, germ cell carcinoma, or neuroendocrine carcinoma, effective treatments are often available. When additional testing does not identify more specific tumor types, some patients with poorly differentiated carcinoma may still be treated successfully with chemotherapy (see Treatment). Squamous cell carcinoma. Nearly 5% to 10% of people with CUP have squamous cell carcinoma. Effective treatments are available for this type of tumor if it has certain characteristics. For instance, if squamous cell carcinoma is found in the cervical (neck) lymph nodes, the primary site is often in the head and neck area. If it is found in the inguinal (groin) lymph nodes, the primary site may be in the vulva, vagina, cervix, anus, or bladder. A careful search is important, particularly since most of these cancers can often be treated successfully. Neuroendocrine carcinoma. Nearly 1% to 5% of people with CUP have neuroendocrine carcinoma. These cancers are being found more often by using a special test called pathologic staining. Some of these tumors are aggressive and fast-growing, but combination chemotherapy (see Treatment) may be effective. Others are very slow-growing, and patients sometimes live for several years even without treatment. Evaluation by an oncologist (called clinical evaluation) Once CUP is diagnosed, an oncologist (a doctor who specializes in treating people with cancer) will do more tests to search for the primary site and to find out how far the cancer has spread. However, for most patients with CUP, the primary site is not found even after extensive evaluation. For this reason, several diagnostic tests may be done to evaluate specific signs and symptoms, including the following: Medical history. The doctor will ask detailed questions about previous illnesses, surgeries, and medications. The doctors can help more if they also know as much information as possible about smoking history, drug use, previous moles or benign (noncancerous) tumors, and any exposure to radiation, asbestos, or other known dangerous chemicals. Giving a complete family history of cancer may also provide your doctor with important clues, especially if one or more siblings, parents, or grandparents have had breast, ovarian, or colorectal cancer. Physical examination. The doctor will do a thorough physical examination of the entire body, including lymph nodes, pelvis, breasts, rectum, and genitals. Blood and urine tests. These tests can find certain tumor markers and proteins that may help determine where the cancer began. Tumor markers are substances found at higher than normal levels in the blood, urine, or body tissues of some people with cancer. Tumor markers are made either by the tumor or by the body as a result of cancer or other conditions. For example, patients who have cancer in the neck lymph nodes and the Epstein-Barr virus (EBV) may have nasopharyngeal cancer. Also, high levels of the proteins human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) may mean a young man with poorly differentiated carcinoma has a germ cell tumor. X-ray. An x-ray is a picture of the inside of the body. For instance, a chest x-ray can help doctors determine if the cancer has spread to the lungs. Computed tomography (CT or CAT) scan of the chest and abdomen. A CT scan helps doctors determine the location of the cancer and where it has spread. A CT scan creates a three-dimensional picture of the inside of the body with an x-ray machine. A computer then combines these images into a detailed, cross-sectional view that shows any abnormalities or tumors. Sometimes, a contrast medium (a special dye) is injected into a patient’s vein to provide better detail. The CT scan can show cancer in the abdomen and chest. Positron emission tomography (PET) scan. A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive substance is injected into a patient’s body. This substance is absorbed mainly by the organs and tissues that use the most energy. Because cancer tends to use energy actively, it absorbs more of the radioactive substance. A scanner then detects this substance to produce images of the inside of the body. PET scans have proven useful for finding a primary site in 20% to 30% of patients with CUP. For this reason, the PET scan is now considered a routine part of the initial evaluation. Even when a primary site is not found, a PET scan can sometimes provide information that is useful in planning treatment. For example, for patients who have one area of cancer where local treatment (surgery or radiation therapy) is being considered, a PET scan can make sure that no other parts of the body have cancer. Using PET and CT scans together provides more detailed and specific information than either test alone. Magnetic resonance imaging (MRI). An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. A small amount of a radioactive substance is injected into a patient’s body and absorbed by the tissues or organs being studied. This substance gives off energy that is detected by a scanner, which produces the images. In some parts of the body, especially the brain and spinal column, MRI provides more information than the CT scan. In addition, women with cancer in the axillary lymph nodes (under the arm) should have a breast MRI scan, since this test can sometimes find a small breast cancer that cannot be seen on a mammogram (x-ray of the breast; see below). Endoscopy. This test allows the doctor to see inside the body with a thin, lighted, flexible tube called an endoscope. The person may be sedated as the tube is inserted through the mouth, down the esophagus, and into the stomach and small bowel. Similar procedures are named according to the part of the body being looked at. For example, a bronchoscopy allows doctors to look inside the bronchial tubes (lungs), and a colonoscopy allows doctors to look inside the colon and rectum. Endoscopy is used for patients with CUP to evaluate the specific symptoms. For instance, patients with squamous cell carcinoma in the neck lymph nodes should always have a complete endoscopy of the nasopharynx, throat, and larynx (voice box) to search for a primary tumor. Prostate-specific antigen (PSA) test. Prostate-specific antigen (a type of protein released by prostate tissue) is a substance found in a man's blood when there is abnormal activity in the prostate, including prostate cancer, benign prostatic hyperplasia (BPH), or prostatitis (inflammation of the prostate). Men who are experiencing bone pain or have metastasis found in their bones will have a PSA test. A PSA test detects higher than normal levels of PSA, which may mean a man has prostate cancer. Mammogram. Women may receive a mammogram (x-ray of the breast), especially if they have cancer in the axillary lymph nodes or other areas that might suggest metastatic breast cancer (for example, fluid around the lungs or spread to the bone). Planning treatment after diagnostic evaluations When the pathologic and clinical evaluations are finished, answers to the following questions are essential in helping doctors plan treatment:
Learn more about what to expect when having common tests, procedures, and scans. Find out more about common terms used during a diagnosis of cancer. Treatment
The treatment of CUP depends on the size and location of the tumor, where else the cancer has spread, and the patient’s overall health. In many cases, a team of doctors will work with the patient to determine the best treatment plan. This section outlines treatments that are the standard of care (the best treatments available) for this specific type of cancer. Patients are also encouraged to consider clinical trials as a treatment option when making treatment plan decisions. A clinical trial is a research study to test a new treatment to prove it is safe, effective, and possibly better than the standard treatment. Your doctor can help you review all treatment options. For more information, see the Clinical Trials section. Chemotherapy is the most common treatment for CUP, and it may get rid of some tumors completely. Since CUP has usually spread to more than one place when diagnosed, this type of tumor can rarely be removed surgically or treated with localized radiation therapy. A description of each treatment option is below, followed by an outline of treatment by the CUP subgroup. Chemotherapy Chemotherapy is the use of drugs to kill cancer cells. Systemic chemotherapy is delivered through the bloodstream, targeting cancer cells throughout the body. Chemotherapy is given by a medical oncologist, a doctor who specializes in treating cancer with medication. Some people may receive chemotherapy in their doctor's office or outpatient clinic; others may go to the hospital. A chemotherapy regimen (schedule) usually consists of a specific number of cycles given over a specific time. The side effects of chemotherapy depend on the individual and the dose used, but can include fatigue, risk of infection, nausea and vomiting, loss of appetite, and diarrhea. These side effects usually go away once treatment is finished. The medications used to treat cancer are continually being evaluated. Learn more about chemotherapy and preparing for treatment. Talking with your doctor is often the best way to learn about the medications you've been prescribed, their purpose, and their potential side effects or interactions with other medications. Learn more about your prescriptions by using searchable drug databases. Radiation therapy Radiation therapy is the use of high-energy x-rays or other particles to kill cancer cells. A doctor who specializes in giving radiation therapy to treat cancer is called a radiation oncologist. A radiation therapy regimen (schedule) usually consists of a specific number of treatments given over a specific time. The most common type of radiation treatment is called external-beam radiation therapy, which is radiation given from a machine outside the body. When radiation treatment is given using implants, it is called internal radiation therapy or brachytherapy. Side effects from radiation therapy may include fatigue, mild skin reactions, upset stomach, and loose bowel movements. Most side effects go away soon after treatment is finished. Learn more about radiation therapy. Surgery A surgical oncologist is a doctor who specializes in treating cancer using surgery. During surgery, the surgical oncologist removes the tumor and an area of tissue around the tumor (called a margin). The extent and location of the surgery depends on where the cancer is found and its size. Learn more about cancer surgery. Treatments by CUP subgroup The following subgroups can often be identified during the initial clinical and pathologic evaluation (see Diagnosis) and have recommended treatments: Women with adenocarcinoma located only in the axillary lymph nodes. Treatment should follow guidelines for stage II breast cancer, even if no primary site in the breast can be found. Local treatment should include mastectomy (surgical removal of the breast) or axillary node dissection (surgical removal of the lymph nodes) plus radiation therapy to the breast. Adjuvant treatment (treatment after surgery) with chemotherapy and/or hormone therapy should also be recommended, depending on the number of lymph nodes with cancer, the estrogen/progesterone receptor status, the HER2 status, and other features of the tumor. Women with peritoneal carcinomatosis (adenocarcinoma on the surface of the abdominal cavity). Treatment should follow guidelines for stage III ovarian cancer, even for women with normal ovaries or whose ovaries have been removed. When possible, debulking surgery (surgery to remove as much of the cancer as possible) should be performed. Chemotherapy with a taxane/platinum combination is recommended after surgery, which is similar to ovarian cancer treatment. CA-125 is often a useful tumor marker for monitoring how well treatment is working. Approximately 20% to 25% of women live a long time after treatment. Young men with poorly differentiated carcinoma found in the mediastinum (center of the chest between the lungs) or retroperitoneum (back of the abdominal cavity). Some men in this group may have germ cell tumors, even if the diagnosis cannot be made. High levels of HCG and AFP in the blood strongly suggest a germ cell tumor. Initial chemotherapy should follow guidelines for treatment of advanced testicular cancer. Removal of the remaining tumor after chemotherapy is often needed. About 30% of men in this group have the cancer successfully treated. Squamous cell carcinoma in the cervical (neck) lymph nodes. Even if a primary site in the head and neck is not found in a careful search, these patients should receive treatment according to guidelines for locally advanced head and neck cancer. This usually includes radiation therapy and chemotherapy given at the same time. For some patients with small cervical lymph nodes with cancer, treatment with radiation therapy alone or surgery followed by radiation therapy is enough. About 40% to 60% of patients in this group live a long time after treatment. Squamous cell carcinoma in the inguinal (groin) lymph nodes. Local treatment should include a lymph node dissection (removal of all inguinal lymph nodes) or radiation therapy. Combining chemotherapy at the same time as radiation therapy should also be considered. Patients who have only a single metastasis. This includes a broad range of patients, since the single metastasis may be found in any part of the body (for example, lymph nodes, brain, lung, or liver). Depending on the location, treatment should include either surgical removal of the tumor or radiation therapy. Most patients in this group eventually develop metastases in other parts of the body, but often after a long time without any disease. Men with metastases only in the bones and/or an elevated PSA level. These patients should be treated with hormone therapy, similar to the treatment recommendations for advanced prostate cancer. Patients with adenocarcinoma in the liver and/or abdomen. In some patients where the tumor spread is only in the abdomen, special pathology tests suggest that the cancer started in the colon. Patients should receive treatment following guidelines for advanced colon cancer. Patients with poorly differentiated neuroendocrine tumors. Although the primary site is usually not found, these types of neuroendocrine tumors often respond to chemotherapy with platinum/etoposide (Etopophos), with or without a taxane (paclitaxel [Taxol] or docetaxel [Taxotere]). This treatment can effectively shrink the cancer and improve cancer-related symptoms for about 60% of patients. A smaller percentage (10% to 15%) of patients in this group has complete shrinkage of cancer with chemotherapy. Patients with poorly differentiated carcinoma. Patients in this group have tumors of many types, and chemotherapy sometimes works well. Patients with certain clinical factors (such as tumors located only in lymph nodes, two or fewer areas of metastasis, and younger age) have better outcomes with chemotherapy. Clinical trials should be offered to all patients in this group. Treatment for those not in a CUP subgroup For a patient whose CUP does not fall into any of the subgroups above, treatment is often less effective. However, many patients can benefit in some way from chemotherapy. Several combinations of chemotherapy have been researched and evaluated in patients with CUP. Usually, these chemotherapy treatment plans contain drugs known to be effective against a variety of cancer types. In particular, combination chemotherapy containing newer drugs has been shown to be more effective and have fewer side effects. Although about 5% of patients given chemotherapy are cured, it can shrink tumors for about 35% to 40% of patients, and 20% to 25% of patients live two years or more after diagnosis. After about four to six weeks of treatment, it is clear which patients are benefiting from treatment; those patients will continue treatment for four to six months. Even for patients whose tumors do not respond to chemotherapy, treatments are available to reduce symptoms. Learn more about treatment of symptoms or palliative care. All patients with CUP should talk with their doctor about participating in a clinical trial that is evaluating new drugs or drug combinations. Many new drugs are being studied, and it is likely that some of these will improve the treatment of patients with CUP. Find out more about common terms used during cancer treatment. Clinical Trials Resources
Doctors and scientists are always looking for better ways to treat patients with CUP. A clinical trial is a way to test a new treatment in order to prove that it is safe, effective, and possibly better than a standard treatment. The clinical trial may be evaluating a new drug, a new combination of existing treatments, a new approach to radiation therapy or surgery, or a new method of treatment or prevention. Patients who participate in clinical trials are among the first to receive new treatments, such as new chemotherapy drugs, before they are widely available. However, there is no guarantee that the new treatment will be safe, effective, or better than a standard treatment. Patients decide to participate in clinical trials for many reasons. For some patients, a clinical trial is the best treatment option available. Because standard treatments are not perfect, patients are often willing to face the added uncertainty of a clinical trial in the hope of a better result. Other patients volunteer for clinical trials because they know that this is the only way to make progress in treating CUP, such as finding new drugs. Even if they do not benefit directly from the clinical trial, their participation may benefit future patients with CUP. Sometimes people have concerns that, by participating in a clinical trial, they may receive no treatment by being given a placebo or a “sugar pill”. The use of placebos in cancer clinical trials is rare. When a placebo is used in a study, it is done with the full knowledge of the participants. Find out more about placebos in cancer clinical trials. To join a clinical trial, patients must participate in a process known as informed consent. During informed consent, the doctor should list all of the patient’s options, so the person understands how the new treatment differs from the standard treatment. The doctor must also list all of the risks of the new treatment, which may or may not be different than the risks of standard treatment. Finally, the doctor must explain what will be required of each patient in order to participate in the clinical trial, including the number of doctor visits, tests, and the schedule of treatment. Learn more about Clinical Trials, including patient safety, phases of a clinical trial, deciding to participate in a clinical trial, questions to ask the research team, and links to find clinical trials. For specific topics being studied for CUP, learn more in the Current Research section. Side Effects
Cancer and its treatment can cause a variety of side effects. However, doctors have made major strides in recent years in reducing pain, nausea and vomiting, and other physical side effects of cancer treatments. Many treatments used today are less intensive but as effective as treatments used in the past. Doctors also have many ways to provide relief to patients when such side effects do occur. Fear of treatment side effects is common after a diagnosis of cancer, but it may be helpful to know that preventing and controlling side effects is a major focus of your health care team. Before treatment begins, talk with your doctor about possible side effects of the specific treatments you will be receiving. The specific side effects that can occur depend on a variety of factors, including the type of cancer, its location, the individual treatment plan (including the length and dosage of treatment), and the person’s overall health. Ask your doctor which side effects are most likely to happen (and which are not), when side effects are likely to occur, and how they will be addressed by the health care team if they do happen. Also, be sure to communicate with the doctor about side effects you experience during and after treatment. Learn more about the most common side effects of cancer and different treatments, along with ways to prevent or control them. In addition to physical side effects, you may experience psychosocial (emotional and social) effects as well. Learn more about the importance of addressing such needs, including concerns about managing the cost of your medical care. For more information on late effects or long-term side effects, please read the After Treatment section or talk with your doctor. After Treatment
After treatment for CUP ends, talk with your doctor about developing a follow-up care plan. This plan may include regular physical examinations and/or medical tests to monitor your recovery for the coming months and years. ASCO offers cancer treatment summary forms to help keep track of the cancer treatment you received and develop a survivorship care plan once treatment is completed. Since patients with CUP are a diverse group of people and recommended treatments vary, the short-term and long-term effects of treatment are different. In addition, recommended follow-up and long-term prognosis varies from person to person. Recommendations in this section are directed primarily to patients who received successful treatment. For patients in specific, treatable subgroups (see Treatment) who receive treatment following guidelines for various cancers of a known primary site, the side effects and after-treatment recommendations are similar to that specific cancer. Please refer to the specific cancer type section for more information. For patients who receive chemotherapy and experience remission (temporary or permanent absence of symptoms), treatment is usually stopped after four to six months. Most of the treatment-related side effects (for example, low blood counts, fatigue, weakness, and joint aches) go away within four to six weeks after treatment. However, peripheral neuropathy (numbness or discomfort in the hands and feet) improves slowly and may take six to 12 months to go away. Close follow-up care is recommended during the first year after treatment ends, with physical examinations and routine laboratory tests every two months, and appropriate x-rays/scans every three to four months. People who were treated for CUP should tell their doctor about any new symptoms right away. People recovering from CUP are encouraged to follow established guidelines for good health, such as avoiding, maintaining a healthy weight, not smoking, eating a balanced diet, and having recommended cancer screening tests. Talk with your doctor to develop a plan that is best for your needs. Moderate physical activity can help you rebuild your strength and energy level. Your doctor can help you create an appropriate exercise plan based upon your needs, physical abilities, and fitness level. Learn more about healthy living after cancer. Find out more about common terms used after cancer treatment is complete. Current Research
Research for CUP is ongoing. The following advances may still be under investigation in clinical trials and may not be approved or available at this time. Always discuss all diagnostic and treatment options with your doctor. Using genetics to diagnose the primary site. Different tissues within the body make different proteins, depending on the genes (this is called gene expression). For example, some of the genes expressed by normal lung cells are different from those expressed by normal colon cells. When cancers develop in these organs, they usually have the same organ-specific pattern of gene expression. It is now possible to analyze a tumor sample (from a biopsy) to find the genes being expressed, which can help find the primary site. The use of these new diagnostic tests, called gene profiling assays, is currently being investigated for patients with CUP. Although information is incomplete, it appears that gene profiling assays will improve diagnosis and guide site-specific treatment for some people with CUP. Several gene profiling assays are available, although they are not yet considered part of standard diagnosis. For patients who are not in any identified CUP subgroup, the following research is being done to find more effective treatments: New combinations of chemotherapy drugs. Many clinical trials are looking at using treatment programs that are effective for other types of cancer. Some of these studies are testing new drugs, such as drugs not yet approved by the U.S. Food and Drug Administration (FDA) and others are looking at new combinations or schedules of approved drugs. Combinations of chemotherapy and targeted therapy. Targeted therapy is a treatment that targets specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. Several targeted therapies are already approved by the FDA for specific cancers, usually for use with chemotherapy. Two such drugs, bevacizumab (Avastin) and erlotinib (Tarceva), have been shown to be effective when used together for CUP. These and other new drugs are in ongoing research. Learn more about targeted therapy. New types of treatment. Patients with cancers that no longer respond to the standard treatment may want to consider clinical trials that test new types of treatment, called phase I clinical trials. The goals of these studies are to find the side effects and best doses for these new drugs, as well as to learn if they are effective against cancer. To find clinical trials specific to your diagnosis, talk with your doctor or search online clinical trial databases now. Questions to Ask the Doctor
Regular communication with your doctor is important in making informed decisions about your health care. Consider asking the following questions of your doctor: During the initial evaluation/staging
Before receiving treatment
Patient Information Resources
In addition to Cancer.Net, there are other sources of information about this type of cancer available online. Cancer.Net maintains a list of national, not-for-profit organizations that may be helpful in finding additional information, services, and support. As always, be sure to talk with your doctor about questions you may have about information you find about this disease. View organizations that offer information on this specific type of cancer. |
