Cancer of Unknown Primary (CUP), also known as “cap cancer,” is diagnosed when metastatic cancer is found in the body, but the original tumor site cannot be identified despite comprehensive diagnostic efforts. This diagnosis presents a challenge because identifying the primary tumor typically guides treatment.
Understanding Cancer with an Unknown Origin
CUP occurs when the original tumor’s location remains elusive. The primary site might be too small to detect with current imaging technologies, it could have regressed spontaneously due to immune system activity, or the metastatic cells may have undergone changes that obscure their origin. CUP accounts for approximately 3% to 5% of all invasive cancer diagnoses. In the United States, around 37,370 cases of CUP are estimated to be diagnosed in 2025. This condition is more common in individuals aged 75 and over, with almost 60% of new cases in the UK diagnosed in this age group.
CUP is broadly categorized based on the microscopic appearance of the cancer cells found in the metastatic tissue. Common classifications include adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma, which describe the cellular characteristics observed under a microscope. Adenocarcinoma is the most frequent subtype, accounting for about 66.6% of CUP cases, followed by squamous cell carcinoma at 13.15%. These classifications help guide further investigations and potential treatment approaches, even when the exact primary site is not found.
The Diagnostic Process
Diagnosis for CUP begins when symptoms arise from metastatic sites, such as a new mass or swelling. A thorough medical history and physical examination are initial steps to gather clues about the cancer’s potential origin. Blood tests, including tumor markers like PSA for prostate cancer or CA-125 for ovarian cancer, may be conducted to provide additional insights.
Imaging scans, such as computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET) scans, are used to search for the primary tumor and map the extent of metastasis. Despite these advanced imaging techniques, the primary tumor often remains undetected. The definitive step in diagnosis involves a biopsy of the metastatic tissue, where a small sample of cancerous cells is removed for laboratory analysis.
Pathologists examine biopsy samples under a microscope and perform specialized tests, including immunohistochemistry (IHC). IHC uses antibodies to identify specific proteins on the surface of cancer cells, providing clues about the tissue of origin. For example, certain patterns of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) staining can help narrow down possibilities, while markers like Hep-Par 1 can indicate a liver origin. This analysis helps classify the cancer type and suggests potential primary sites, even if the original tumor is too small or has regressed.
Treatment Strategies
Treatment for Cancer of Unknown Primary is guided by the presumed origin of the cancer, the type of cancer cells identified, and the extent of its spread. A multidisciplinary team of specialists, including oncologists, radiation oncologists, and surgeons, collaborates to develop the treatment plan. Chemotherapy is a common treatment, often involving platinum agents combined with other drugs like paclitaxel or gemcitabine.
Radiation therapy may be used to manage localized cancer or symptoms like pain. Newer radiation techniques, such as intensity-modulated radiation therapy (IMRT) and proton therapy, can deliver precise doses to tumors while sparing surrounding healthy tissues. In cases where the cancer is confined to a single area, such as lymph nodes, surgery might be an option, sometimes followed by radiation therapy to eliminate any remaining cancer cells.
Targeted therapy and immunotherapy have expanded treatment possibilities. Targeted therapies interfere with specific proteins or pathways that promote cancer cell growth, while immunotherapy harnesses the body’s immune system to fight the cancer. Molecular profiling of biopsy samples can identify specific gene changes, which may make a patient eligible for these treatments, including clinical trials.
Prognosis and Living with the Diagnosis
The prognosis for Cancer of Unknown Primary varies, influenced by factors such as the specific cell type, the extent of metastasis, and how the cancer responds to treatment. The average survival time for CUP is approximately 9 to 12 months after diagnosis. However, some favorable-risk subsets of CUP, such as isolated axillary lymph node metastases in women, can have a better outlook.
Supportive care plays a role in managing CUP, focusing on relieving symptoms and improving the patient’s quality of life. It includes pain management, anti-sickness medications, and bone-strengthening drugs. Emotional support for patients and their families is important for comprehensive care. Many organizations offer resources and programs to assist individuals through their treatment journey.
Follow-up care is tailored to the individual’s situation, monitoring for disease progression and managing any side effects of treatment. Clinical trials continue to be an avenue for advancing new therapies and improving outcomes for patients with CUP. Participation in these trials offers access to innovative treatments and contributes to an understanding of this disease.