Carcinoma of unknown primary (CUP) is defined as metastatic carcinoma with no identifiable primary malignancy after a thorough diagnostic workup.
1 Approximately 3% to 5% of all diagnosed cancers are classified as CUP.
2 Adenocarcinoma, squamous cell carcinoma (SCC), poorly differentiated carcinoma, and neuroendocrine carcinoma are the primary histologies classified as CUP. Lymphoma, melanoma, and sarcoma have stage-specific therapies; therefore, these diseases are excluded from this group. A number of theories exist to explain CUP. One theory is that the primary lesion metastasized before necrosis occurred; therefore, the primary lesion is no longer identifiable when the metastatic tumor is detected. A second theory is that the primary cancer is microscopic; however, its metastasis is able to proliferate into a more significant tumor in different tissues. CUP presents a unique set of diagnostic and treatment circumstances for patients.
THE DIAGNOSTIC PROCESS
A thorough history, physical examination, and selection of diagnostic tests are necessary to determine a differential diagnosis for the origin of disease. Symptoms, including hematuria, cough, hematochezia, and melena, can provide clues to the possible primary tumor. The patient's age, risk factors, and work or hobby exposures must also be considered. The most significant aspect of the patient's history is a family history of cancer, particularly any cancers in first-degree relatives. For example, Lynch syndrome should be considered in persons with a strong family history of early-onset colon cancer, or if the patient has a significant family history of malignancies that are associated with Lynch syndrome (such as endometrial, ureteral, ovarian, or small-bowel cancer). A complete physical examination must be performed, even if the patient does not have any symptoms. All patients should have a rectal examination. Prostate and genitalia examinations should be performed on all men. If symptoms and test results in women suggest a gynecologic malignancy, pelvic examinations should be performed. A breast examination should be performed on all women with adenocarcinoma CUP.
Imaging A thorough search for the primary tumor via imaging studies should be undertaken in all patients, including a CT of the chest, abdomen, and pelvis. The role of positron emission tomography combined with CT (PETCT) imaging technology is controversial, and reimbursement can present a challenge. PET-CT is proven helpful in locating primary disease in the head and neck region in patients with a tissue
diagnosis of SCC. In a retrospective review by Kothari and colleagues, 18F-fluorodeoxyglucose activity seen on PET-CT identified ipsilateral tonsillar tumors as the primary source in three of five patients with CUP manifesting with cervical lymphadenopathy.
3 Based on these findings, tonsillectomy is recommended for patients who have cervical CUP because the potential primary may be small, undetectable tumors in the deep crypts of the tonsils.
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Women with CUP should have a recent mammogram. If mammogram results indicate that isolated axillary lymph nodes are involved, MRI and ultrasound of the breasts may be warranted to search for small or poorly visualized primary tumors in the breast.
Laboratory tests and tumor markers Laboratory studies, including liver and kidney function tests and a CBC, should be ordered to evaluate for underlying microcytic anemia. Serum tumor markers (carcinoembryonic antigen, carbohydrate antigen [CA] 19-9, CA 125, and CA 27.29) are nonspecific but can provide prognostic insight and indicate response to treatment (
Table 1). However, these tests are rarely helpful with the diagnosis of the primary malignancy. Men should have prostate-specific antigen levels measured; if elevated, a prostate biopsy is warranted. An alpha-fetoprotein (AFP) level higher than 400 µg/L and presence of cirrhosis and a liver mass are suggestive of a hepatocellular carcinoma. AFP levels can be elevated along with beta-human chorionic gonadotropin (beta-hCG) in patients with testicular tumors when the pathology is undifferentiated or poorly differentiated carcinoma.
Other studies Patients should have a recent colonoscopy with verification that the endoscope reached the cecum. An upper endoscopy is warranted if pathology results, imaging studies, or symptoms are suspicious of an esophageal or gastric primary tumor. A triple endoscopy (laryngoscopy, esophagoscopy, bronchoscopy) may be indicated for patients with neck lymphadenopathy. Suspicious sites and common sites for malignancy should be biopsied.
PATHOLOGY AND IMMUNOHISTOCHEMISTRY
Sixty percent of tumors in patients with CUP are adenocarcinomas. SCC constitutes about 5% of tumors and the remaining 35% are poorly differentiated carcinomas, poorly differentiated adenocarcinomas, and poorly differentiated neoplasms. A small percentage of tumors are neuroendocrine cancer, mixed lineage tumors (adenosquamous, sarcomatoid carcinomas), and undifferentiated neoplasms.
The pathologist makes the vital initial interpretation of the tissue, but valuable information can also be obtained with additional staining of tissue samples (Table 2). Tissue is usually acquired by fine needle aspiration or core needle biopsy. A core needle biopsy obtains a larger sample and is preferred in cases of CUP. If the initial sample contains a significant amount of necrotic tissue, a repeat biopsy is recommended. Immunohistochemistry is not 100% specific or sensitive but is helpful in determining tumor lineage.2 More than 20 types of cytokeratin (CK) filaments with distinct molecular weights aid in identifying the origin of the disease. CK7 is present in patients with lung, endometrial, ovarian, or breast cancer; CK20 is present in the urothelium, Merkel cells, and the lower GI epithelium.5 Some patterns of staining are highly suggestive of tumor origin. For example, CK7–/CK20+ suggests a colorectal cancer profile; in contrast, CK7+/CK20– is associated with lung, breast, upper GI, pancreas, and biliary tract cancer profiles.5