Cancer of unknown primary (CUP) is a metastatic cancer that has no identified site of origin following the completion of a standard oncologic evaluation. CUPs are a heterogeneous group of cancers with different histopathologies and varied manifestations. Collectively, CUPs account for approximately 3–5% of all malignancies. The initial diagnostic workup of CUP is focused on trying to locate the site of the primary tumor based on the imaging and histopathology findings. If a primary site cannot be identified, the cancer is classified into a favorable or unfavorable subgroup. CUPs in the favorable subgroup have clinical manifestations, histopathology findings, or biomarkers similar to known primary cancers and are treated with standard anticancer treatment regimens for the equivalent primary cancer. Patients with a tumor in the unfavorable subgroup (80–85%) receive empiric low-dose chemotherapy, but the median survival is poor (typically less than one year).
- Incidence: 4.1 per 100,000 (account for 3–5% of all malignancies worldwide) 
- Median age at diagnosis: 65 years 
- Sex: slight preponderance in men 
Epidemiological data refers to the US, unless otherwise specified.
- Clinical features are extremely variable depending on the location of metastatic disease and include: 
- Pain (60%)
- Abdominal symptoms (40%)
- Palpable lymphadenopathy (20%)
- Pathological fractures or bony pain (15%)
- Chest symptoms (15%)
- Symptoms related to CNS lesions, e.g., seizures, focal neurological deficit (5%)
- Constitutional symptoms secondary to advanced cancer may be present.
- Work up for the most likely primary cancer based on symptoms.
- If symptoms are nonspecific, consider common origins of cancer metastases.
- In palpable lymphadenopathy, consider patterns of lymphatic drainage to determine a likely primary cancer.
- No primary site identified: Perform routine studies for CUP.
- Primary site remains unknown: Perform additional studies based on presentation and histopathology.
Routine studies for CUP 
- Assessment for organ/marrow involvement: CBC, CMP, liver chemistries
- Prognostication: LDH 
- All patients: CT thorax, abdomen, and pelvis with IV contrast
- Women and transmen: mammography
Analysis of the tumor 
- Well-differentiated or moderately well-differentiated adenocarcinomas (∼ 60%)
- Poorly differentiated carcinoma (25–30%)
- Squamous cell carcinoma (5%)
- Undifferentiated neoplasm (5%)
- Neuroendocrine (1%)
- Immunohistochemistry: e.g., cytokeratin, vimentin (see “Immunohistochemical markers”)
- Gene expression assay
- Molecular profiling
Patients who have had a mastectomy should have an MRI to assess residual breast tissue.
Additional studies 
- Women and transmen with axillary adenocarcinoma: MRI breast
- Midline neoplastic disease: alpha-fetoprotein, hCG
- Men and transwomen with adenocarcinoma metastatic to bone: prostate-specific antigen (PSA)
- Neuroendocrine tumor: octreotide scan, chromogranin A
- Cervical lymph node squamous cell carcinoma: laryngoscopy and PET-CT scan 
- Abdominal symptoms: colonoscopy and gastroscopy
- Hilar or mediastinal lymph node involvement: bronchoscopy
Peripheral blood tumor markers should not be performed routinely because they are frequently not specific for tumor sites. They may, however, be helpful in certain clinical presentations. 
PET-CT scan may be useful in patients with CUP who have cervical adenopathy or a single metastatic tumor site; it has limited utility in other patients. 
- Refer patients to specialist treatment centers when possible.
- Determine the treatment regimen.
- Classify the CUP into favorable or unfavorable subgroups based on the predicted response to anticancer therapy.
- Perform prechemotherapy screening to determine eligibility for treatment.
- Discuss treatment options, including clinical trials, with patients to facilitate shared decision-making. 
- Consider early referral to palliative care to assist with complications of cancer.
Favorable subgroup of CUP 
- CUPs with clinical manifestations, histopathology findings, or biomarkers consistent with a specific tissue of origin and likely to respond to site-specific anticancer therapy 
- Account for 15–20% of CUPs 
- Managed with anticancer treatment similar to that given for an equivalent primary neoplasm
- Long-term disease control is possible in 30–60% of patients. 
|Management of favorable subgroup of CUP |
|Squamous cell carcinoma affecting nonsupraclavicular cervical lymph nodes|| |
Treat as head and neck squamous cell carcinoma.
|Colorectal immune or molecular markers are present||Treat as colorectal cancer.|
|Cancers with isolated axillary lymph node involvement in women and transmen||Treat as breast cancer.|
|Papillary or serous peritoneal carcinoma in women and transmen||Treat as ovarian cancer.|
|Bone metastases and elevated PSA in men and transwomen||Treat as prostate cancer.|
|Midline lymph node involvement in men and transwomen||Treat as germ cell tumor.|
|Neuroendocrine cancers (well-differentiated and poorly differentiated)||Amenable to empiric chemotherapy|
|Cancers with a single metastatic deposit||Amenable to resection and/or radiotherapy with/without empiric chemotherapy|
Unfavorable subgroup of CUP
- Cancers with none of the features of a favorable CUP
- Account for the majority (80–85%) of CUPs 
- Treat with empiric, low-toxicity chemotherapy (typically cisplatin and an additional agent). 
- Consider surgery or radiation therapy in localized disease. 
Targeted therapy based on the results of gene expression assays and molecular testing in CUP is unproven but rapidly evolving. 
- Typically poor
- Favorable subgroup of CUP: variable, typically the same as that of metastatic disease from a similar known primary cancer 
- Unfavorable subgroup of CUP: median survival < 1 year