Cancer of unknown primary origin
|Cancer of unknown primary origin|
|Classification and external resources|
Cancer of unknown primary origin (CUP), malignancy of undefined (primary) origin (MUO), or occult primary tumor is diagnosed when metastatic cancer is found but the place where the cancer began (the primary site) cannot be determined.
Before saying for certain whether a cancer is truly of unknown primary origin, a number of investigations can be performed, such as medical imaging and examination of biopsy samples with immunohistochemistry techniques and potentially gene expression profiling. Based on the site of the disease and results of these investigations, 20 to 25% of people are classified to have a favorable prognosis and the remainder a poorer outlook. The investigations determine the nature of treatment, which generally consists of chemotherapy.
About three to five percent of all cancer patients have a cancer whose primary site is never identified. It is the seventh or eighth most common cancer diagnosis.
Signs and symptoms
Cancer of unknown primary origin usually comes to attention because of masses or swellings found somewhere in the body, either by physical examination or on medical imaging performed for another indication. The disease typically develops rapidly, and tumor deposits may occur in places in the body that are otherwise unusual. Comprehensive physical examination is part of the process to identify a possible primary source of cancer; this should include the breasts, lymph nodes, the skin, external genitals, as well as an internal examination of the rectum and of the pelvic organs.
The location of tumor deposits may be a clue as to the underlying source, even if this cannot be found on investigations. For instance, a woman in whom there is axillary lymphadenopathy (swelling in the lymph nodes of the armpit) it is likely that the cancer originated in the breast, and men with lymph node deposits in the mediastinum of the chest and/or retroperitoneal space of the abdomen may have a germ cell tumor.
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Cancer of unknown primary source is not a single type of cancer, although researchers have attempted to find a common characteristic that explains why a cancer might spread very early without causing symptoms at the site of origin.
CUP may be classified by its appearance under a light microscope. The majority of cancers of unknown primary, about 90%, are adenocarcinomas, with 60% appearing as moderately to well-differentiated adenocarcinoma, while about 30% are poorly differentiated adenocarcinoma. The term adenocarcinoma refers to cancer that begins in the cells in glandular structures in the lining or covering of certain organs in the body. Common primary sites for adenocarcinomas include the lung, pancreas, breast, prostate, stomach, liver, and colon.
The remaining 10 percent are either poorly or undifferentiated malignant neoplasms (5%), or squamous cell carcinomas (5%). Rarely, CUP may appear as neuroendocrine tumors, or mixed tumors, such as sarcomatoid, basaloid, or adenosquamous carcinomas.
In recent years, microscopic and other diagnostic techniques have improved dramatically. For this reason, it is now possible to determine the primary site in about four out of five cases initially diagnosed as CUP. In some cases, the part of the body where cancer cells are first discovered helps the doctor decide which diagnostic tests will be most helpful. Additional clues which may be helpful in determining the primary site include the pattern of spread, and the cell type, which is based on its appearance under a microscope (histology).
The initial work-up of a cancer of unknown primary includes a CT scan of the chest, abdomen, and pelvis, with IV contrast. Women with enlarged lymph nodes (lymphadenopathy) confined to the axillary region with CUP should have a mammogram or ultrasound to evaluate for possible breast cancer. If those imaging studies are normal, then an MRI of the breast may be appropriate. A PET CT scan should be done for squamous cell carcinoma involving lymph nodes of the neck region. For other types of cancer of unknown primary, a PET-CT offers uncertain benefit.
The pattern of spread may suggest the location of the primary site. For example, metastatic cancer found in the upper body is more likely to have an origin above the diaphragm, at sites such as the lung and breast. If the metastatic cancer appears first in the lower part of the body, the primary cancer is more likely to be at sites below the diaphragm, such as the pancreas and liver.
When the cancer cells are poorly differentiated (that is, they look less evolved than normal cells when viewed under a microscope), the cancer may be either a lymphoma or a germ cell tumor. Lymphomas begin in the lymphatic system. Germ cell tumors usually begin in the ovaries and testes.
In patients in whom the primary cancer is eventually found, the lung and pancreas are the most common primary cancer sites. CUP also may be traced to the breast, prostate, colon, or rectum as the primary site.
Sometimes, however, even when doctors use very sophisticated methods to try to identify the primary site, the part of the body the cancer cells came from cannot be determined. About 2 to 4 percent of all cancer patients have a cancer whose primary site is never found.
Identifying the primary tumor site is important because knowing its location and type often helps doctors plan the best treatment. Treatment that is specific to the suspected type of cancer is likely to be more effective. Still, when diagnostic tests have not identified the primary site, doctors must decide whether the potential benefits of more extensive testing outweigh a patient’s discomfort, possible complications, and the financial costs.
Antibodies may be used to determine the expression of protein markers on the surface of cancer cells. Often the expression of these antigens is similar to the tissue that the cancer grew from, so immunohistochemical testing sometimes helps to identify the source of the cancer. Individual tests often do not provide definitive answers, but sometimes patterns may be observed, suggesting a particular site of origin (eg lung, colon, etc.). Immunohistochemical testing suggests a single source of cancer origin in about one in four cases of CUP. However, there is a lack of definitive research data showing that treatment guided by information from immunohistochemical testing improves outcomes or long-term prognosis.
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CUP is a term that refers to many different cancers. For that reason, treatment depends on where the cancer is found, the microscopic appearance of the cancer cells, the biochemical characterization of the cells, and the patient’s age and overall physical condition. In women, who present with axillary lymph node involvement, treatment is offered along the lines of breast cancer. In patients, who have neck lymph node involvement, then treatment is offered along the lines of head and neck cancer. If inguinal lymph nodes are involved, then treatment may be offered along the lines of genitourinary cancer.
If the site of origin is unknown or undiscovered, then the histology of the tumor (e.g., adenocarcinoma, squamous cell or mesenchymal) can usually be identified, and a probable origin may be assumed. When this is possible, then treatment is based on the type of cell and probable origin. Based on histological subtype, combination chemotherapy may be selected. A combination of carboplatin and paclitaxel is often used. Advances techniques such as FISH and tissue of origin testing may also be employed. Germ cell tumors often carry abnormality of chromosome 12, which if identified, directs treatment for metastatic germ cell tumors.
No method is standard for all forms of CUP, but chemotherapy, radiation therapy, hormone therapy, and surgery may be used alone or in combination to treat patients who have CUP. Even when the cancer is unlikely to be cured, treatment may help the patient live longer or improve the patient’s quality of life. Radiation may be used to shrink a variety of local tumors. However, the potential side effects of the treatment must be considered along with the potential benefits.
The uncertainties and ambiguity inherent in a CUP diagnosis may cause additional stress for the patient.
Most people with cancer of unknown primary origin have widely disseminated and incurable disease, although a few can be cured through treatment. With treatment, typical survival with CUP ranges from 6 to 16 months. Survival rates are lower in cases with visceral metastatic disease, ranging from 6 to 9 months. Survival rates are higher when the cancer is more limited to lymph nodes, pleura, or peritoneal metastasis, which ranges from 14 to 16 months. Long-term prognosis is somewhat better if a particular source of cancer is strongly suggested by clinical evidence.
Around 9,800 people were diagnosed with cancer of unknown primary in the UK in 2011, and around 10,625 people died from the disease in 2012.
From 1980 to 1990, definition of unknown primary cancer was based on imaging results. Subsequently, research on immunohistochemistry allowed for the classification of cancer of unknown primary into sub-types. From 2000 to 2010, tailored therapies began to evolve, targeting specific subtypes of unknown primary.
Notes and references
- Pavlidis N, Pentheroudakis G (April 2012). "Cancer of unknown primary site". Lancet 379 (9824): 1428–35. doi:10.1016/S0140-6736(11)61178-1. PMID 22414598.
- National Institute for Health and Clinical Excellence. Clinical guideline 104: Metastatic malignant disease of unknown primary origin. London, 2010.
- Varadhachary, Gauri R.; Raber, Martin N. (21 August 2014). "Cancer of Unknown Primary Site". New England Journal of Medicine 371 (8): 757–765. doi:10.1056/NEJMra1303917.
- Ettinger, David S.; Agulnik, Mark; Cates, Justin M. M.; Cristea, Mihaela (December 2011). "Occult primary". Journal of the National Comprehensive Cancer Network: JNCCN 9 (12): 1358–1395. ISSN 1540-1413. PMID 22157556.
- "Cancer of unknown primary statistics". Cancer Research UK. Retrieved 27 October 2014.