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 accounts for between 3% and 5% of all cancer cases worldwide.
Cancer originates where cells begin to multiply uncontrollably and can spread to other parts of the body. Regardless of where it is when diagnosed, it is named after the location where it started. A lung tumor that has spread to the liver, for example, 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 as a metastasis but its primary location cannot be defined, it is a cancer of unknown primary site. If after some tests doctors can locate where the cancer originated, it is named according to that location.
The main reason for the importance of knowing the tumor’s original location is to determine the treatment plan – some respond better to chemotherapy, others to hormonal 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 the microscope;
- Laboratory and imaging test results; and
- Information about the patient’s organs that have already been or are currently affected by tumors.
The risk factors that most likely contribute to the development of cancer of unknown primary site are:
- Diabetes mellitus;
- Smoking;
- Obesity; and
- Family history of cancer.
Main types of cancer of unknown primary site
In an initial microscope analysis, the cells of a cancer of unknown primary site are classified into one of the following categories:
- Adenocarcinoma – develops from glandular cells and accounts for approximately 60% of cases of cancer of unknown primary site;
- Undifferentiated carcinoma – there are enough details to say that it is a carcinoma, but its cells are too irregular to classify further. It accounts for about 30% of cases of cancer of unknown primary site. When further analyzed, about 10% of them end up being identified as lymphoma, melanoma, or sarcoma;
- Squamous cell carcinoma – tumors resemble cells from the surface of the skin or linings of some organs;
- Poorly differentiated malignant neoplasm – there is no doubt that it is cancer, but the cells are so irregular that the pathologist cannot determine the type of cell from which they may have originated. After more detailed examinations, most are identified as lymphoma, sarcoma, or melanoma, and some as carcinomas; and
- Neuroendocrine carcinoma – rare tumors that begin in neuroendocrine system cells. These cells do not form an organ, such as 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 an unknown primary site tumor depend on the organs to which it has spread. Some signs that something may be wrong and lead to a diagnosis include:
- Persistent pain in a particular area of the body (such as abdomen, chest, or bones);
- Swollen lymph nodes;
- Abdominal mass;
- Persistent cough and shortness of breath;
- Skin tumors;
- Intestinal and bladder dysfunction;
- Anemia and weakness;
- Fatigue;
- Unexplained loss of appetite and weight loss;
- Recurrent fever and night sweats;
- Unusual bleeding and discharge.
Diagnosis
The fact that it is a very heterogeneous disease makes the diagnosis of cancer of unknown primary site quite challenging.
In the presence of symptoms that suggest the possibility of the patient having cancer, a clinical examination is performed and blood tests are requested:
- Complete blood count – to measure blood cells; and
- Blood chemistry – to show the functioning of some organs, such as the liver.
Imaging tests may also be requested to assist in the diagnosis of cancer of unknown primary site. They help locate the lesion and are useful for 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 potential tumors in the lungs;
- Upper gastrointestinal series – X-ray exam 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;
- Computed tomography (CT) – with or without contrast, to visualize small slices of body regions and, in some cases, to precisely guide the positioning of a biopsy needle in an area suspected of cancer;
- Magnetic resonance imaging (MRI) – produces images that allow understanding 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 positioning of a biopsy needle in a suspected cancer nodule;
- Positron emission tomography (PET scan) – measures variations in biochemical processes that, when altered by a disease, occur before they are visible signs in computed tomography or magnetic resonance imaging images. It also allows detecting if cancer has spread to lymph nodes or other structures and organs of the body;
- Somatostatin receptor scintigraphy (OctreoScan) – useful for the diagnosis of neuroendocrine pancreatic tumors; and
- Endoscopy – allows visualization of the mucosa, aiding in the diagnosis of cancer and/or in determining the extent of the disease.
The previously mentioned exams – physical, blood, and imaging – can detect the presence of cancer, but in most cases, a biopsy is necessary to confirm the cancer of unknown primary site.
The types of biopsies that can be performed are:
- Fine-needle aspiration biopsy – aspirates a sample of the tumor tissue for analysis and is usually guided by computed tomography;
- Core needle biopsy – uses a large-caliber needle, allowing a larger sample of tissue to be taken;
- Excisional biopsy – the 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 into deep planes, in which only a part of the tissue is removed;
- Endoscopic biopsy – the endoscope has lenses or a camera at the tip and can also be used to remove the lesioned tissue;
- Thoracentesis or paracentesis – used in cases of pleural effusion to remove a sample of abnormal fluid; and
- Biopsy and bone marrow aspiration – used to check if cancer cells have spread to the bone marrow and to internal soft tissues of certain bones.
If the diagnosis from the biopsy is inconclusive, further tests are conducted, such as immunohistochemistry, flow cytometry, cytogenetics, molecular genetics, gene expression profiling, and electron microscopy.
After all these tests, if there is no conclusive origin, the pathologist will classify the cancer of unknown primary site and its type.
Staging of cancer of unknown primary site
Regarding the staging of cancer of unknown primary site, that is, the stage at which it is (from I to IV, with I being the least advanced and IV having widespread dissemination), it is common for this disease to be in stage II, III, or IV at the time of diagnosis, since cancer of unknown primary site is, by definition, a metastatic cancer.
Treatment
From 15% to 20% of patients with cancer of unknown primary site have a favorable prognosis – meaning they have chemosensitive and possibly curable tumors. They are treated similarly to patients with metastases from known equivalent primary tumors.
The other 80% to 85% of patients do not have a good prognosis – the disease shows modest sensitivity to cancer therapies. For them, palliative chemotherapy is recommended to maintain quality of life during the estimated survival period (around 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 early stages and have not confirmed the benefit of adopting treatment guided by molecular tests for patients with this diagnosis.
