Carcinoma of unknown primary (CUP) is a biopsy-proven (mainly epithelial) malignancy for which the anatomic site of origin remains unidentified after an intensive search. CUP is one of the 10 most frequently diagnosed cancers worldwide, accounting for approximately 3–5% of all cancers. Most investigators do not include lymphomas, metastatic melanomas, and metastatic sarcomas that present without a known primary tumor as CUP because these cancers have specific stage- and histology-based treatments that guide management.
With the increasing availability of additional sophisticated imaging, invasive diagnostic techniques, and the emergence of effective targeted therapies in several cancers, an individualized management algorithm with an impact on quality of life and survival is critical. The reasons cancers present as CUP remain unclear. One hypothesis is that the primary tumor either regresses after seeding the metastasis or remains so small that it is not detected. It is possible that CUP falls on the continuum of cancer presentation where the primary has been contained or eliminated by the natural body defenses. Alternatively, CUP may represent a specific malignant event that results in an increase in metastatic spread or survival relative to the primary. Whether the CUP metastases truly define a clone that is genetically and phenotypically unique to this diagnosis remains to be determined.
No characteristics that are unique to CUP relative to metastases from known primaries have been identified. Abnormalities in chromosomes 1 and 12 and other complex cytogenetic abnormalities have been reported. Aneuploidy has been described in 70% of CUP patients with metastatic adenocarcinoma or undifferentiated carcinoma. The overexpression of various genes, including Ras, bcl-2 (40%), her-2 (11%), and p53 (26–53%), has been studied in CUP samples, but they have no effect on response to therapy or survival. The extent of angiogenesis in CUP relative to that in metastases from known primaries has also been evaluated, but no consistent findings have emerged.
Obtaining a thorough medical history from CUP patients is essential, paying particular attention to previous surgeries, removed lesions, and family medical history to assess potential hereditary cancers. Physical examination, including a digital rectal examination in men and breast and pelvic examinations in women, should be performed. Determining the patient's performance status, nutritional status, comorbid illnesses, and cancer-induced complications is essential since these may affect treatment planning.
Role of Serum Tumor Markers and Cytogenetics
Most tumor markers, including CEA, CA-125, CA 19-9, and CA 15-3, when elevated, are nonspecific and not helpful in determining the primary tumor site. Men who present with adenocarcinoma and osteoblastic metastasis should undergo a prostate-specific antigen (PSA) test. In patients with undifferentiated or poorly differentiated carcinoma (especially with a midline tumor), elevated β-human chorionic gonadotropin (βhCG) and α fetoprotein (AFP) levels suggest the possibility of an extragonadal germ cell (testicular) tumor. Cytogenetic studies had a larger role in the past, although interpretation of these older studies can be challenging. In our opinion, with the availability of immunohistochemical stains, cytogenetic analyses are indicated only occasionally. We reserve them for undifferentiated neoplasms with inconclusive immunohistochemical stains and those for which a high suspicion of lymphoma exists.
Chest x-rays are always obtained in CUP workups but are often negative, especially with low-volume disease. A CT scan of the chest, abdomen, and pelvis is indicated in the search for the primary, evaluate the extent of disease, and select the most favorable biopsy site. Older studies suggested that the primary tumor site is detected in 20–35% of patients who undergo a CT scan of the abdomen and pelvis, although by current definition these patients would not be considered as having CUP. Older studies also suggest a latent primary tumor prevalence of 20%; with more sophisticated imaging, this prevalence is <5% today.
Mammography should be performed in all women who present with metastatic adenocarcinoma, especially in those with adenocarcinoma and isolated axillary lymphadenopathy. MRI of the breast is a recognized follow-up modality in patients with suspected occult primary breast carcinoma following a negative mammography and sonography. The results of these imaging modalities can influence surgical management; a negative breast MRI result predicts a low tumor yield at mastectomy.
A conventional workup for a squamous cell carcinoma and cervical CUP (neck lymphadenopathy with no known primary tumor) includes a CT scan or MRI and invasive studies, including indirect and direct laryngoscopy, bronchoscopy, and upper endoscopy. Ipsilateral (or bilateral) tonsillectomy (with histopathology) has been recommended for these patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) scans are useful in this patient population and may help guide the biopsy; determine the extent of disease; facilitate the appropriate treatment, including planning radiation fields; and help with disease surveillance. A smaller radiation field encompassing the primary (when found) and metastatic adenopathy decreases the risk of chronic xerostomia. Several studies have evaluated the utility of PET in patients with cervical CUP. These trials have included a small number of patients; primary tumors were identified in ∼21–30%.
The diagnostic contribution of PET to the evaluation of other CUP (outside of the neck adenopathy indication) is controversial. PET-CT can be helpful for patients who are candidates for surgical intervention for solitary metastatic disease because the presence of disease outside the primary site may affect surgical planning.
Invasive studies, including upper endoscopy, colonoscopy, and bronchoscopy, should be limited to symptomatic patients or those with laboratory, imaging or pathologic abnormalities that suggest that these techniques will result in a high yield in search for a primary cancer.
Pathologic Diagnosis of CUP
A detailed pathologic examination of the most accessible biopsied tissue specimen is mandatory in CUP patients. Pathologic evaluation typically consists of hematoxylin-and-eosin stains and immunohistochemical tests. Electron microscopy and cytogenetics are rarely useful.
Light Microscopy Evaluation
Adequate tissue obtained by fine-needle aspiration or core-needle biopsy ...