Unknown primary carcinoma : Unknown primary cancer

What is Carcinoma of Unknown Primary?

A carcinoma of unknown primary is a cancer that presents with distant metastases (spread of tumor) and the source of the cancer or primary site remains unknown. It is usually detected by a biopsy from a part of the body that does not produce that type of cancer, and no site of origin is identified, despite a thorough physical examination including breast, pelvic and rectal exam, basic laboratory tests, urinalysis, x-rays and other imaging studies.

Carcinomas of unknown primary site (CUPS) are the seventh most common malignancy. No primary site of origin can be identified in 3 to 5 percent of patients diagnosed with metastatic cancer. CUPS encompasses a wide range of different tumor types and characteristics. They vary in many ways including clinical presentation (findings on a physical examination as well as symptoms the patient describes), histological appearance (how the biopsy tissue sample looks under the microscope) and natural history (how the cancer behaves). The treatment as well as prognosis varies significantly. Since the disease is diagnosed at a metastatic stage, the prognosis is generally poor. However, some tumor types can be well treated, with symptoms relieved and can occasionally be cured (e.g. germ cell tumors, choriocarcinomas, and lymphomas).

What are the Symptoms of Carcinoma of Unknown Primary?

There are many ways a person with carcinoma of unknown primary may present to the physician. Initial symptoms are related to the metastatic sites and/or tumor host's inflammatory interactions, which lead to symptoms of loss of appetite, weight loss and fatigue. The following are examples of symptoms that relate to the site of the metastatic tumor:

• bloating, swollen abdomen, nausea and vomiting may suggest cancers within the lining of the abdomen
• bone pain usually at night, progressive pain localized or worse with weight bearing may suggest bone metastases
• cough and shortness of breath may suggest lung metastases
• headaches, focal weakness, changes in thought processes (cognitive changes) may suggest brain metastases

How to Diagnose Carcinoma of Unknown Primary?

In trying to discover the primary site, there are two important considerations.

1. Some primary cancers are much more treatable than others are. These include cancers of the breast, prostate, thyroid, and ovary; lymphomas; as well as germ cell tumors similar to those that develop in the testes. Efforts are made to determine if one of these is the primary site. Not only is the prognosis much better with these types of cancer, but the treatment has to be specific for that cancer.
2. There are important clues that can be used to determine the primary site. One clue is the location of the metastases. The most common sites of CUPS are metastases to the lung, lymph nodes, bone and liver. When CUPS is found in the upper part of the body, the most common source is the lung. When it is found in the liver, the usual primary site is the gastrointestinal tract, including the pancreas. Another clue is the type of pathology - the findings by the pathologist when examining the biopsy specimen.

Once metastatic carcinoma is found further testing will be based upon history and physical examination, as well as localizing symptoms.

Examples:

• If axillary (under the arm) lymph nodes are involved in a female, then a mammogram or breast ultrasound will be checked.
• If high neck lymph nodes were involved with squamous carcinoma, an endoscopy including examination of the nose, throat, tongue, lung and esophagus are indicated.
• If the patient presents with symptoms of concern for brain metastasis, an MRI of the brain as well as CT scans of the chest or abdomen to look for a primary site.
• A male presenting with enlarged lymph nodes in the neck/shoulder region or under the arm will require a CT scan of the chest, abdomen and pelvis.
• Bone metastases in older males will require a bone scan, PSA and prostate biopsy.

Approximately one third of patients whose primary site remains undetected by history and physical exam, chest x-ray, and laboratory studies will have the primary site detected by CT scan of the chest, abdomen and pelvis. PET scan has been used to stage the extent of disease. The PET scans ability to detect the primary site has had variable success. PET scans have also been used to screen for head and neck primaries but does not appear to contribute to CT scans or MRIs of the head and neck. Those who have been extensively investigated for carcinoma of unknown primary will have a pancreatic or lung cancer primary 40% of the time.

Blood and other tests

• Complete blood counts
• Urinalysis to check for blood
• Test to check for hidden (occult) blood in the stool
• Blood chemistry tests to check liver and kidney function
• Tests for serum tumor markers that may be elevated with specific cancers such as prostate-specific antigen - PSA (prostate), alpha-fetoprotein (hepatoms, germ-cell tumors), and thyroglobuoin and calcitonin (thyroid gland) are not specific enough to help to identify a primary site. Other commonly used blood tumor markers (CA19.9, CA125, CA15.3 CEA) are frequently elevated but are non-specific. However, these may be useful in following response to treatment. These tests may be obtained when there is clinical suspicion but they do not help in determining tumor location, nor do they eliminate the need for a biopsy.

Biopsy

A biopsy is usually recommended to get a sample of the tissue. This may be done with a needle (with or without x-ray, CT scan or ultrasound guidance) or with a surgical procedure. The information obtained from the pathologic examination of the biopsy tissue may establish a primary site. The pathologist has a crucial role in the diagnosis, by evaluating the biopsy specimen and determining not only if it is malignant (cancerous) but, based on his or her experience and the tissue's appearance under the microscope, the most likely source. The pathologist may be consulted before the biopsy is done because some of the methods used to evaluate the tissue require special preparation of the tissue at the time of the biopsy. The special methods used by the pathologist in evaluating the tissue sample may include special stains, electron microscopy (increases the magnification of the cells), or methods to evaluate the genetic material of the specimen.

Common subsets of CUPS include adenocarcinoma, squamous carcinoma and poorly differentiated neoplasm. Adenocarcinoma is the most common. The pattern of adenocarcinoma does not have features that are distinctive enough to separate them into different primary sites. This is when special pathologic methods may have an important role in helping to determine the primary site, or to rule out certain sites.

Twenty to 30% of CUPS are poorly differentiated cancers. This means that the cells do not resemble normal cells at all. However, within this group there may be cancers such as lymphomas, germ cell tumors and neuroendocrine tumors that may be highly responsive to certain treatments. Again the pathologist's role is an important one.

What are the Treatment Options?

There is no generally recommended treatment for all patients with CUPS. Treatment is based on many factors. If there is a likely primary site, based on the clinical presentation, pathology findings, as well as on the clinical, laboratory and imaging studies, the treatment will be given according to that probable diagnosis.

In patients who do not fit into any probable diagnosis categories, a trial of combination chemotherapy may be appropriate unless they are very ill (confined to bed) as a result of the cancer. Those who are unable to tolerate chemotherapy would be managed with aggressive symptom management and possibly radiation therapy to a specific tumor that is causing problems (i.e. pain, compression) when indicated.

In trying to discover the primary site, there are two important considerations:

1. Some primary cancers are much more treatable than others are. These include cancers of the breast, prostate, thyroid, and ovary; lymphomas; as well as germ cell tumors similar to those that develop in the testes. Efforts are made to determine if one of these is the primary site. Not only is the prognosis much better with these types of cancer, but the treatment has to be specific for that cancer.
2. There are important clues that can be used to determine the primary site. One clue is the location of the metastases. The most common sites of CUPS are metastases to the lung, lymph nodes, bone and liver. When CUPS is found in the upper part of the body, the most common source is the lung. When it is found in the liver, the usual primary site is the gastrointestinal tract, including the pancreas. Another clue is the type of pathology - the findings by the pathologist when examining the biopsy specimen.