All About Cancer of Unknown Primary
What is a Cancer of Unknown Primary and how common is it?
A cancer can start anywhere in the body and can spread to another area of the body. When cancer spreads, the cells from both areas (the original area and where it has spread to) look the same under a microscope. For example, if a lung cancer spreads to the bone, a biopsy of that bone lesion will look like lung cancer cells, and the pathologist will report that this cancer is a metastasis from a primary lung cancer (meaning a cancer that started in the lung but spread elsewhere). In some cases, the picture is not so clear and the pathologist cannot determine from what organ or body site those metastatic cells originated. In that case, the cancer is called a "cancer of unknown primary" (CUP). CUP is a metastatic cancer that has been diagnosed by a biopsy but the primary location, or the place where the cancer started, cannot be identified.
CUPs comprise 4-5% of invasive cancers. These cancers tend to be underreported because they can be misdiagnosed. In 2009, the number of new cases of CUP was approximately 31,490. Approximately 10% of patients with CUP have a prior history of cancer, and the average age at diagnosis is between 59 and 66 years old. Men and women are affected equally.
What symptoms can I have?
Many patients with CUP can have symptoms that are similar to patients with widespread or advanced cancer. Patients may have general deterioration, fatigue, weight loss, digestive symptoms (constipation, poor appetite, diarrhea), abdominal pain, difficulty breathing, or symptoms related to an enlarged liver, fluid in the abdomen, or swollen lymph nodes.
Where in my body can CUPs be found?
A CUP could technically be found anywhere in the body, although common sites include: lymph nodes, liver, bone, lung or lung lining (pleura), brain, abdominal cavity, adrenal gland or skin. These locations are the sites that many cancers commonly spread to, making it difficult to determine where the cancer originated.
How are CUPs evaluated?
The healthcare provider will perform a comprehensive patient interview and physical exam to determine which laboratory or radiology tests are needed. All men should receive a prostate exam and all women should undergo a breast and pelvic exam. Blood tests looking for abnormalities in the blood are often performed. Ultimately, a biopsy is required to determine the cell type, which may help in finding the primary location. Future testing depends on the cell type of tumor determined after biopsy.
When a biopsy of a CUP is obtained, a pathologist examines it under a microscope. The pathologist may determine the cancer's cell type by how it appears or using special stains that highlight certain traits of the cell. Determining the cell type of the CUP can guide further evaluation and potential treatment. Cell type can be classified in one of the following categories:
- Squamous cell carcinoma
- Neuroendocrine carcinoma
- Poorly differentiated tumors
The sections below describe how further testing and treatment decisions are guided using the cell type.
Adenocarcinoma represents about 70% of all CUPs. Several types of cancer can be adenocarcinomas, including colorectal, prostate, pancreatic, lung, breast, ovarian, esophageal and stomach, and knowing this can help narrow the search for the primary tumor site.
A CT scan of the abdomen, can find the primary site of the tumor in 10-35% of patients with adenocarcinoma. A colonoscopy may be done to look for colon cancer, particularly if the patient has experienced blood in the stool. Positive emission tomography (PET) imaging can locate the primary tumor in 20-30% of cases. PET imaging highlights tissues that utilize sugars rapidly. Cancers are detectable by PET imaging because they constantly metabolize sugar as they grow and divide, more so than normal tissues.
A prostate specific antigen (PSA) should be ordered in men to rule out prostate cancer. If there are enlarged lymph nodes in the armpit area, known as the axillary region, the possibility of metastatic breast cancer should be investigated. Tumor markers (CEA, CA 19-9, CA-125, CA15-3) are substances that are often elevated in the blood when a particular type of cancer is present; for example, in colon cancer, CEA is often elevated. However, these markers are also often elevated in CUP and have not been found to be very helpful for identifying the original site of cancer. Certain tumors can create a specific protein on their surface, which can be detected in the biopsy sample using a special test called immunohistochemistry (IHC), performed by the pathologist.
Neuroendocrine tumors (NETs) represent approximately 1% of all CUPs. These types of tumors are further classified into either low- or high-grade based on the appearance of the cells under the microscope. This categorization is important for the required work up and treatment of NETs. Neuroendocrine tumors can occur in many areas of the body, including the lung, bowel, pancreas, appendix, liver, gallbladder, adrenal gland, kidney, pituitary gland, thyroid, and parathyroid.
The initial approach for evaluating a low-grade NET includes radiology tests and blood and urine tests for certain tumor markers, which can be elevated in some cancers. Eighty percent of low grade NETs express high amounts of a protein on its surface, which binds to a hormone called somatostatin. Somatostatin can be tagged with a radioactive label, which can be visualized using a radiology scan called Octreoscan, which may locate a primary site. A CT scan or MRI of the abdomen is frequently done because the intestinal tract is a common primary site for low-grade NETs. If these tests are unsuccessful in finding the primary site, endoscopy of the upper and lower GI tract is performed, which can be effective for finding pancreatic NETs. If a patient presents with facial-flushing and weight loss, a low-grade NET called carcinoid tumor should be suspected. Blood and urine tests for 5-hydroxyindoleacetic acid (5-HIAA) should be checked, as these are elevated in many carcinoid tumors.
High-grade neuroendocrine tumors are more aggressive and typically appear in multiple sites of the body, including the liver, bone, lung and brain. Initial evaluation should include either MRI or PET/CT scan of the chest, abdomen, and pelvis. Octreoscans are not effective for detecting high grade NETs. A brain MRI is occasionally performed as high grade NETs can spread to brain.
Squamous Cell Carcinoma
Squamous cell carcinomas (SCC) account for 5% of CUPs. SCCs can occur in the head and neck, lung, skin, cervix, vagina, vulva and anus. SCCs typically present as swollen lymph nodes. The location of the enlarged lymph nodes dictates the recommended diagnostic tests.
Head to mid-neck: A patient history should attempt to identify a source such as previous skin cancer. A history of smoking raises the suspicion for head & neck cancer. A thorough scalp and skin exam should be performed along with examination of the tongue, nose cavity, throat, and mouth with a fiberoptic camera/scope. A CT scan or MRI of the neck is also a necessary part of the workup. If both are negative, a PET scan should be performed. Without PET, almost 30% of cancers can be missed. PET scans are also able to find metastatic areas of disease. Finally, testing for viral DNA (e.g. HPV) in the biopsy can guide the clinician to the location of the primary tumor.
Lower neck to clavicle: Enlarged SCC lymph nodes in this region are primarily due to lung or head & neck cancers. This prompts a thorough head & neck exam, along with a CT scan of the chest. If physical exam and CT scan are unremarkable, PET CT scan or a bronchoscopy may be done to further evaluate.
Groin: Enlarged lymph nodes found in the groin mandates examination of the genital and rectal/anal areas. In women, a pelvic exam is essential. Any masses found while performing the physical exam should be biopsied.
Poorly Differentiated Carcinomas
Poorly differentiated carcinomas account for 20-25% of CUPs . These tumors are classified as poorly differentiated because they cannot be characterized during examination under the microscope. These tumors should be well evaluated by the pathologist because there are many treatable cancers that can be classified as poorly differentiated. A majority of poorly differentiated carcinomas will be able to be better described as a germ cell tumor, melanoma, lymphoma or sarcoma. While the primary site of these cancers may not be found, knowing this tumor classification allows for effective treatment decisions.
Initial evaluation may include CT, PET scan or MRI of the abdomen & chest to look for a primary site or enlarged lymph nodes. Blood tests for human chorionic gonadotropin (hCG) and alpha-fetal protein (AFP) should be measured, as these two markers are elevated in germ cell tumors, which are a common type of poorly differentiated carcinoma. The biopsy specimen should be further evaluated using immunohistochemistry (IHC) tests to detect markers (substances) found on the outside of the cells of certain tumor types.. For example, a subtype of melanoma has been known to express S100 protein and vimentin. Other cancers that may be classified by IHC include lymphomas and sarcomas.
What happens if the primary tumor is found?
The patient would typically receive the indicated treatment for the primary cancer discovered.
How are CUPs treated if a primary tumor is not found?
Treatment of CUP is dependent on the tissue type on biopsy (adenocarcinoma, SCC, poorly differentiated carcinoma, NET) and the patient's site of disease.
Adenocarcinoma: Within adenocarcinoma, there are can be specific subgroups of patients. These subgroups can be used to guide treatment.
Women with peritoneal carcinomatosis: When cancer is located on the lining of the abdominal wall, outside the intestinal tract, it is known as peritoneal carcinomatosis. These tumors often share biological similarities to ovarian cancer. Therefore the treatment is similar to advanced ovarian cancer. Surgical removal of the tumor is the first line recommended therapy. Some patients also respond well to chemotherapy after surgery with a survival of up to six to seven years.
Women with adenocarcinoma in the axillary lymph nodes: This is most commonly seen in patients with breast cancer. Therefore, the biopsy specimen is tested for breast cancer markers (estrogen receptor, progesterone receptors, HER2). Radiology tests (e.g. mammography, US, MRI) looking for primary breast cancer are also performed. However, if a primary breast cancer cannot be found, the cancer may still be treated as a breast cancer with surgery, radiation and/or chemotherapy, if indicated.
Men with adenocarcinoma detected in bone metastases: Several cancers can present with bone metastases in men including lung, prostate, liver, kidney, thyroid, and colon. An elevated PSA tumor marker (blood test) may result in treating the man for prostate cancer. Without an elevated PSA, further testing may be done to find another metastasis or the primary site, in order to better guide treatment.
Some patients may present with a "colon cancer profile," which includes metastatic liver and/or peritoneal (lining of the abdomen) disease, adenocarcinoma that has similar qualities to a colon cancer when viewed under a microscope, or colon cancer markers on tissue staining (CD20 or CDX2 positive, CD7 negative). These patients should receive a combination of chemotherapy for metastatic colon cancer, including folinic acid (vitamin supplemental), fluorouracil (chemotherapy), oxaliplatin (2nd chemotherapeutic agent), and bevacizumab. Bevacizumab is a type of targeted therapy that binds to growth factors, ultimately inhibiting the growth of blood vessels (anti-VEGF) that the tumor needs to grow.
Adenocarcinoma without a suspected primary site: If no primary site of disease is found (or strongly suspected), resection of the tumor is usually performed. If resection is not an option because of the location of the disease, radiation therapy should be considered. The role of chemotherapy after surgery is not well defined.
NET: Treatment varies depending on the grade of the tumor previously discussed in the evaluation section of this article.
Treatment of low-grade NETs of unknown primary is dependent on where the disease is found and the extent of the tumor. In patients with disease limited to the liver, chemoembolization can be performed, which involves local delivery of chemotherapy to the tumor followed by obliteration of its blood supply. Surgery may be an option in limited disease. Both targeted and traditional chemotherapy agents and medications that target somatostatin (Octreotide) may be used to manage systemic disease.
For high-grade NETs, treatment is approached similarly to extensive stage small cell lung cancer, as these cancers have similar histology. Treatment includes standard chemotherapy medications used to treat lung cancers, including cisplatin, carboplatin, etoposide, irinotecan and paclitaxel
SCC: Similarly to the evaluation, the treatment for SCCs is dependent on the location of the enlarged lymph nodes.
Head to mid neck: The best treatment is not known, however, the goal is to remove or control the known cancer and to prevent the primary site from further developing. Treatment may include surgery, with or without radiation and/or chemotherapy or radiation therapy alone.
Lower neck to clavicle: If lung cancer is found on imaging or bronchoscopy, then treatment for lung cancer should be initiated. For non-detectable disease, the treatment approach is similar to cancerous lymph nodes in the head to mid neck region mentioned above.
Groin: If a primary cancer is not found, surgical removal of cancerous lymph nodes, followed by radiation therapy, can lead to long-term survival.
Poorly differentiated carcinoma: If the primary source of tumor is not identified, chemotherapy hoping to treat the primary cancer is administered. This method of treatment is known as empiric therapy. Patients are most commonly started on platinum chemotherapy agents. Although some patients can display complete response, median survival is approximately eight to ten months.
What is the future of diagnosis and treatment for CUPs?
Molecular profiling focuses on finding the DNA expressed in a particular tumor. Understanding the genes of a CUP can help to identify its origin and further guide treatment. In the past, molecular profiling was not possible because obtaining an adequate biopsy sample was difficult. However, with improvements in technology, it is currently feasible and studies have found gene expression assays are able to predict the tumor origin in 75% to 90% of samples. Molecular profiling has recently begun to be implemented in the clinical workup of CUPs, with associated improved patient survival.
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