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The types of treatment used for a cancer of unknown primary (CUP) depend on several factors, including the size and location of the cancer, the results of lab tests, and how likely it is to be a certain type of cancer. Your overall health, ability to tolerate treatment, and personal preferences matter also. If the origin of the cancer can be determined during testing, the cancer would be treated according to where it started.

Squamous cell carcinomas in neck lymph nodes

These cancers usually begin somewhere in the mouth, throat, or larynx. The primary site is found in most patients during a full endoscopic examination of potential sites of origin in the throat, pharynx, and larynx.

When no primary site is identified, treatment should follow guidelines for stage II squamous cancer of the head and neck. Location and extent of the tumor in the neck are used to determine if radiation therapy, surgery, or a combination of treatments is the best  option. For most patients, internal radiation to the affected side of the neck and potential primary sites in the throat and larynx is given with chemotherapy as the initial therapy. When tumors are very large or present on both sides of the neck, chemotherapy (chemo) and radiation therapy are often used together.

The outlook for these patients depends on the size, number, and location of the lymph nodes containing metastatic cancer. Overall, more than half of these patients remain cancer-free after initial therapy. For more information about the usual treatments for these cancers see Nasal Cavity and Paranasal Sinus Cancers, Oral Cavity and Oropharyngeal Cancer and Laryngeal and Hypopharyngeal Cancer. 

Adenocarcinomas in underarm lymph nodes

Most cancers that have spread to the axillary lymph nodes under the arm in women are breast cancers. If CUP is found in the axillary nodes, the recommended treatment is similar to that for women with stage II breast cancer.

Treatment options include surgical removal of the breast, called a mastectomy,  and/or surgery to remove axillary nodes called an axillary lymph node dissection plus radiation therapy to the breast. Chemotherapy, hormone therapy, and/or HER2-targeted therapy may be recommended after surgery. This depends on the patient’s age and whether the cancer cells contain estrogen and/or progesterone receptors or the HER2 protein.

Sometimes these treatments are given before surgery to shrink the tumor and make surgery easier or more effective.  For more information about prognosis and treatment of breast cancer that has spread to the lymph nodes, see Breast Cancer.

Although cancer in axillary lymph nodes in men might  haves pread from a breast cancer, spread from a lung cancer is much more likely. Complete pathologic evaluation, including molecular cancer classifier assays (MCCA) and comprehensive molecular profiling (CMP), is used to predict the tissue of origin.

If no other metastases are identified, these patients fit into the “single metastasis” subgroup, and local therapy with axillary lymph node dissection and/or radiation therapy to the underarm area may be considered.

If molecular testing strongly indicates a lung cancer, treatment as a stage IV lung cancer would also be considered.

Cancer in groin lymph nodes

It’s important to search carefully for the origin of these cancers, as many of them can be treated effectively if they are found. If the primary tumor cannot be found, surgery is usually the main treatment.

If the cancer appears to be confined to a single lymph node, removing it may be the only treatment needed. In other cases, more extensive surgery called a lymph node dissection may be needed. If more than one lymph node is found to have cancer cells, radiation therapy and/or chemotherapy may be recommended as well.

Cancer in the peritoneum (lining of the abdominal and pelvic cavities)

Unless tests have found a primary cancer outside the ovaries (in which case the diagnosis of CUP would no longer apply), these cancers are most likely to be spread from either ovarian cancer, fallopian tube cancer, or primary peritoneal carcinoma (PPC). Fallopian tube cancer and PPC are diseases similar to ovarian cancer, and they are all treated the same way.

Treatment is typically surgery to remove the uterus, both ovaries, both fallopian tubes, and as much of the cancer as possible, followed by 6 to 8 months of chemotherapy as used for ovarian cancer. Additional treatment should also follow guidelines for advanced ovarian cancer.

Cancer in the retroperitoneum (back of the abdomen) or mediastinum (middle of the chest)

If lab tests of the tumor sample rule out lymphoma, the most likely diagnosis is a germ cell tumor, especially in younger men. High levels of HCG and AFP tumor markers in the blood strongly suggest a germ cell tumor. People with this subtype usually get chemotherapy according to the guidelines for the treatment of later-stage testicular cancer. After chemotherapy, surgery to remove any remaining cancer is often needed.  Even cancers in these areas that do not have lab results typical of germ cell tumors often respond to chemotherapy combinations for treating testicular germ cell tumors. More information about the treatment of germ cell tumors can be found in Testicular Cancer and Ovarian Cancer.

If a carcinoma is found in the mediastinum in an older patient, it is unlikely to be a germ cell tumor and should be further evaluated with MCCA and CMP. If a primary site is suggested, treatment should follow guidelines for that tumor type.

Melanoma in lymph nodes only

Once a CUP has been diagnosed as a melanoma, it’s no longer a true CUP. This situation is mentioned, nonetheless, because some tests to identify melanomas may take several days. Until the results come in,  these patients are considered to have CUP.

The recommended initial treatment of melanoma of unknown primary with only lymph node spread should follow guidelines for stage II melanoma. Treatment includes surgery to remove the lymph nodes in the affected area and, in some cases, systemic treatment with immunotherapy or BRAF inhibitors. For more information see Melanoma Skin Cancer.

Cancer in other locations such as bone or liver

For nearly 7 out of 10 people with adenocarcinoma of unknown primary, the cancer does not fit into any specific clinical subgroups. These patients usually have metastases in several areas, often the liver and bone. Until recently, the standard treatment recommendation for these patients was chemotherapy, using combinations of drugs that work for several types of cancer. However, improved diagnostic tests and treatment options for many cancer types also have resulted in identifying more effective treatment for many people with CUP.

Site-specific and molecularly targeted treatment of CUP

In recent years, new testing methods and technologies have become available that identify the primary site in most patients with CUP. For patients who do not fit into any of the specific subsets, identifying the tissue of origin is a major advance in the treatment of CUP. These patients can now receive site-specific treatment instead of chemotherapy. Recent clinical trials have confirmed the superiority of this approach.

In recent years, treatments have improved for most types of cancer. In addition to chemotherapy, standard treatments often include immunotherapy and/or targeted agents. For example, standard treatment for adenocarcinoma of the lung now includes specific chemotherapy (different from the typical broad CUP regimens), immunotherapy, and targeted therapy for subgroups with cancers that show molecular abnormalities. Standard second- and third-line (alternative treatments when the first or second treatments aren't successful) treatments also exist for these lung cancers.

As new drugs continue to be identified for specific cancer types, their use in treating CUP with the same predicted tissue of origin is likely to improve treatment results.