What is cancer of unknown primary site
Cancer of unknown primary site is a cancer that can be histologically and clinically verified, but only its metastases are found at the time of diagnosis – the tumor from which it originated is not detectable. It is responsible for between 3 and 5% of all cancer cases in the world.
Cancer originates where cells begin to multiply uncontrollably, potentially spreading to other parts of the body. Regardless of where the cancer is located when diagnosed, it is named after where it first started in the body. For example, a lung tumor that has spread to the liver is classified as metastatic lung cancer, not liver cancer.
However, in some cases it is not clear where the cancer originated. If the tumor is found to have metastasized but its primary site cannot be defined, it is classified as a cancer of unknown primary site. If after tests are performed and doctors are able to locate where the cancer originated, it is named after that location.
The main reason why it is important to know where the tumor originates is to establish the line of treatment – some respond better to chemotherapy, others to hormone therapy. But even if it is not possible, there are methods to define the ideal protocol.
The following factors provide the necessary clues for the medical team to choose the best treatment:
- The appearance of cancer cells under microscope;
- The results of laboratory and imaging tests; and
- Information about the patient’s organs that have been or are currently affected by tumors.
The risk factors that most likely support the development of cancer of unknown primary site are the following:
- Diabetes mellitus;
- Obesity; and
- Family history of cancer.
Main types of cancer of unknown primary site
After a primary microscopic analysis, cells from a cancer of unknown primary site are classified into one of the following categories:
- Adenocarcinoma – develops from glandular cells and represents approximately 60% of cases of cancer of unknown primary site;
- Poorly differentiated carcinoma – when there is enough detail to say it is a carcinoma, but the cells are too irregular to carry out any further classification. It represents about 30% of cancer cases of unknown primary site. When in-depth analyses are carried out, about 10% of them end up being identified as lymphoma, melanoma or sarcoma;
- Squamous cell carcinoma – when tumors look like cells on the surface of the skin or the linings of some organs;
- Poorly differentiated malignant neoplasm – there is no doubt that this is cancer, but the cells are so irregular that the pathologist cannot define the type of cell from which they may have originated. After more detailed examinations are performed, most are identified as lymphoma, sarcoma or melanoma, and some as carcinomas; and
- Neuroendocrine carcinoma – these are rare tumors that start in the cells of the neuroendocrine system. These cells do not form an organ, like the adrenal glands or thyroid, and are scattered throughout other organs, such as the esophagus, stomach, pancreas, intestines, and lungs. This variation of tumors represents a small number of cases of cancer of unknown primary site.
Symptoms and signs of cancer of unknown primary site
The symptoms of cancer of unknown primary site depend on the organs to which it has spread. The following are some of the signs that may indicate that something is wrong and lead to the diagnosis:
- Persistent pain in some area of the body (abdomen, chest or bones, for example);
- Swollen lymph nodes;
- Abdominal mass;
- Persistent cough and shortness of breath;
- Skin tumors;
- Intestinal and bladder dysfunction;
- Anemia and weakness;
- Unexplained lack of appetite and weight loss;
- Recurrent fever and night sweats;
- Unusual bleeding and discharge.
The fact that it is a very heterogeneous disease makes the diagnosis of cancer of unknown primary site quite challenging.
When symptoms that indicate the possibility that the patient has cancer are reported, a clinical examination is performed and the following blood tests are requested:
- Complete blood count – to measure blood cells; and
- Blood biochemistry – to examine the functioning of some organs, such as the liver.
Imaging tests may also be prescribed to aid in the diagnosis of cancer of unknown primary site. They help locate the lesion and are useful in determining the extent of the disease and its staging. The main imaging tests related to cancer of unknown primary site are:
- Chest X-ray – detects possible tumors in the lungs;
- Upper gastrointestinal series – X-ray examination with barium contrast to evaluate the esophagus, stomach and the first part of the small intestine and define possible abnormalities in the lining of these organs;
- CT scan – with or without contrast, to visualize small slices of body regions and, in some cases, to accurately guide the placement of a biopsy needle in an area with suspected cancer;
- Magnetic resonance imaging – produces images that help to determine the size and location of the tumor, as well as the presence of metastases;
- Ultrasound – produces real-time images of organs, tissues and blood flow and can also accurately guide the placement of a biopsy needle in a suspected cancerous nodule;
- Positron Emission Tomography (PET Scan) – measures variations in biochemical processes that, when altered by disease, occur before they are visible signs on CT or MRI images. It also allows to detect whether the cancer has spread to lymph nodes or other structures and organs in the body;
- Somatostatin receptor scintigraphy (OctreoScan) – useful for the diagnosis of pancreatic neuroendocrine tumors; and
- Endoscopy – allows visualization of the mucosa, helping to diagnose cancer and/or determine the extent of the disease.
Exams – physical, blood and imaging – can detect the presence of cancer, but in most cases a biopsy is required to confirm cancer of an unknown primary site. The following are the types of biopsy that can be performed:
- Fine needle aspiration – a sample of tumor tissue is removed for analysis and examination is usually guided by computed tomography;
- Core needle biopsy – by using a large gauge needle, it allows a larger tissue sample to be removed;
- Excisional biopsy – most common type of biopsy, in which an incision is made in the skin and the entire tumor or lymph node is removed;
- Incisional biopsy – usually performed for larger lesions, which are ulcerated or have grown in a deep plane, in which only part of the tissue is removed;
- Endoscopic biopsy – the endoscope has lenses or a camera at the end and can also be an instrument to remove injured tissue;
- Thoracocentesis or paracentesis – used in cases of pleural effusion to remove an abnormal fluid sample; and
- Bone marrow biopsy and aspiration – used to check whether cancer cells have spread to the bone marrow and to the internal soft tissues of certain bones.
If the biopsy diagnosis is not conclusive, other tests are performed, such as immunohistochemistry, flow cytometry, cytogenetics, molecular genetics, gene expression profile and electron microscopy.
After all these tests are performed, if there is no conclusive origin, the pathologist will classify the cancer as an unknown primary site and determine its type.
Regarding the definition of the staging of cancer of unknown primary site, that is, the stage in which it is found (from I to IV, with I being the least comprehensive and IV the one that already has a wide spread), it is normal that this disease be at stage II, III, or IV at the time of diagnosis, as cancer of unknown primary site is, by definition, a metastatic cancer.
From 15 to 20% of patients with cancer of unknown primary site have a favorable prognosis – this means they have chemosensitive and possibly curable tumors. They are treated similarly to patients with equivalent known primary tumor metastases.
The other 80 to 85% of patients do not have a good prognosis – the disease has modest sensitivity to therapies used against cancer. For them, the use of palliative chemotherapy is recommended, so that they have a better quality of life in the estimated survival period (about one year).
A new perspective in the treatment of patients diagnosed with cancer of unknown primary site would be the application of molecular tests and the evaluation of biomarkers to promote more specific approaches with potential benefit for these patients. However, studies are still in the initial stage and have not confirmed the benefit of adopting treatment guided by molecular tests for patients with this diagnosis.