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Based on the classification and the location of the metastatic cancer of unknown primary, doctors decide which additional tests should be done. For example, a poorly differentiated malignant neoplasm may be tested further to try to classify it more precisely as a melanoma, lymphoma, sarcoma, small cell carcinoma, germ cell tumor, etc. The classification and location also help the doctor decide what other imaging tests may be helpful in looking for the primary site.
Some of the more common ways in which cancer of unknown primary may appear are listed with a brief description of what testing may be done.
Cancer that has spread to neck nodes usually comes from cancers of the mouth, throat, sinuses, salivary glands, larynx (voice box), thyroid, or lung. Tests will be done to look at these areas thoroughly for signs of where the cancer may have started.
The type of cancer is also a clue about where the cancer might have started. Most cancers of the mouth, throat, and larynx are squamous cell carcinomas. Lung cancer and cancer of the sinuses can be squamous cell carcinomas or adenocarcinomas. Salivary gland cancers are often a type of adenocarcinoma. Thyroid cancer can spread to neck lymph nodes. When it looks similar to normal thyroid tissue, it’s easy to know where it came from. It can also look like adenocarcinoma. Cancers from all of these sites can also be poorly differentiated carcinomas or even poorly differentiated malignant neoplasms.
The base of the tongue, the throat, and the larynx are deep inside the neck and not seen easily. Indirect pharyngoscopy and laryngoscopy use small mirrors to look at these areas. A fiberoptic laryngoscope (a flexible, lighted, tube inserted through the mouth or nose) can be also be used to look in those areas, as well as deeper in the throat, if needed.
If the cancer is likely to have started in the head and neck area, the mouth, throat, larynx, esophagus (tube that connects the mouth to the stomach), trachea (wind pipe), and bronchi (tubes leading from the trachea to the lungs) will be examined very thoroughly. This exam, called panendoscopy, is done in the operating room while you are under general anesthesia (asleep).
Imaging tests like CT or MRI scans of the sinuses and neck area may be used to look for small cancers that may have already spread to lymph nodes in the neck. A PET scan (or combined PET/CT scan) may be done as well.
A chest CT scan and bronchoscopy (viewing the air passages through a flexible lighted tube) are often recommended to find suspected lung cancers that may have been missed by a routine chest x-ray.
Ultrasound or CT of the neck may be used to look for thyroid cancer.
In women, cancer that has spread to underarm (axillary) nodes is most likely to have started in the breast, so a thorough breast physical exam is always done. Then diagnostic mammography (breast x-ray) and breast ultrasound are often the first tests ordered. If no tumor is found on these tests, an MRI of the breasts may be very useful.
Lab tests on the tumor cells can determine if they have estrogen receptors (ER) and/or progesterone receptors (PR). These receptors are often found in breast cancers, and finding them may help confirm the diagnosis of breast cancer. The presence of these receptors is also important in planning treatment, as cancers containing these receptors are likely to respond to hormone therapy.
If a breast cancer diagnosis cannot be confirmed, tests to look for lung cancer may be done. Lung cancer is the most common cause of cancer spread to underarm lymph nodes in men, and can also be the cause in women.
The most likely starting places of these cancers are the vulva, vagina, cervix, penis, skin of the legs, anus, rectum, or bladder, but other places are also possible.
The ovaries and fallopian tubes are the most likely source of a cancer that has spread in this way, but cancers from the breast, lung, or digestive tract can also spread here. Tests for CA-125 in the blood and tumor samples are positive in most ovarian and fallopian tube cancers, and can be used to help determine whether the primary tumor is likely to be from there or some other organ. CT scans of the abdomen and pelvis are also usually done.
Most cancers that start in the peritoneum (lining of the pelvis) look and behave like a cancer that started in the ovary and spread. They also cause CA-125 levels to go up. These cancers are called primary peritoneal carcinoma and are treated like ovarian cancer.
More information about ovarian, fallopian tube, and primary peritoneal cancers can be found in Ovarian Cancer.
Germ cell tumors are one of the types of cancer that can start in these locations, especially in younger people. Most germ cell tumors develop from germ cells in the gonads (testicles or ovaries), but these cancers can sometimes start in other parts of the body, including the mediastinum (which is in the chest).
Results of blood tests and stains of the cancer cells for alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) are often positive in germ cell tumors. Cytogenetic or molecular studies may also find chromosomal changes that support a diagnosis of germ cell tumor.
In men, especially those who are younger or who have abnormal levels of AFP and/or HCG, ultrasound of the scrotum may be done to see if the cancer may have started in the testicles.
CT scans of the chest, abdomen, and pelvis are typically used to try to exclude other types of cancers (such as lung cancer). In women, tests may be done to see if the cancer started in the breast or ovaries.
It’s important to identify germ cell tumors because they often respond well to certain combinations of chemotherapy drugs with good outcomes and sometimes, cures.
A thorough exam of the skin, nails, and other body surfaces such as the eye and the inside of the mouth is needed to look for the primary melanoma. Some primary melanomas that have already spread might be quite small or look like ordinary moles to the untrained examiner. Rarely, primary melanomas go away on their own without treatment after spreading, leaving behind only an area of slightly lighter colored skin.
Treatment of Melanoma depends on whether it has spread only to lymph nodes or whether internal organs are also involved. Chest x-rays, CT scans of the head and abdomen, and blood tests are usually done to see if cancer can be found anywhere else in the body.
The main goal in trying to determine the source of a CUP is to see if you have a cancer that may respond well to specific treatments. Some of the most important cancers to identify include thyroid, breast, and prostate cancers:
Well differentiated neuroendocrine cancers can sometimes show up as liver metastases first (with no clear primary site). The source for these may be the pancreas (pancreatic neuroendocrine tumors), the gastrointestinal (GI) tract, or rarely, the lungs. These cancers tend to be slow growing and may respond to drug treatment.
A type of poorly differentiated malignant neoplasm called small cell carcinoma or poorly differentiated neuroendocrine carcinoma can develop in the lungs and, less often, in other organs. Some of these cancers usually respond to certain chemotherapy combinations, although they are likely to come back (recur) at a later time.
The American Cancer Society medical and editorial content team
Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing.
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Last Revised: March 9, 2018
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