Carcinoma of an unknown primary site is a common clinical syndrome, accounting for approximately 3% of all oncologic diagnoses. Patients in this group are heterogeneous, having a wide variety of clinical presentations and pathologic findings. A patient should be considered to have carcinoma of an unknown primary site when a tumor is detected at one or more metastatic sites, and routine evaluation (see below) fails to define a primary tumor site.

Although all patients with cancer of an unknown primary site have advanced, metastatic disease, universal pessimism and nihilism regarding treatment are inappropriate. Subsets of patients with specific treatment implications can be defined using clinical and pathologic features. In addition, trials of empiric chemotherapeutic regimens incorporating new antineoplastic agents have suggested improved response rates and survival in unselected groups of patients with carcinoma of an unknown primary site.

Epidemiology

Gender Unknown primary cancer occurs with approximately equal frequency in men and women and has the same prognosis in the two genders.

Age As with most epithelial cancers, the incidence of unknown primary cancer increases with advancing age, although a wide age range exists. Some evidence suggests that younger patients are more likely to have poorly differentiated histologies.

Disease sites Autopsy series performed prior to the availability of CT resulted in the identification of a primary site in 70%-80% of patients. Above the diaphragm, the lungs were the most common primary site, whereas various GI sites (pancreas, colon, stomach, liver) were most common below the diaphragm. Several frequently occurring cancers, particularly breast and prostate cancers, were rarely identified in autopsy series.

With improved radiologic diagnosis, the spectrum of unknown primary cancer has probably changed. Limited recent autopsy data suggest a lower percentage of primary sites identified, particularly in patients with poorly differentiated histology.

Signs and symptoms

Patients with unknown primary cancer usually present with symptoms related to the areas of metastatic tumor involvement.

Sites of metastatic involvement include the lungs, liver, and skeletal system; therefore, symptoms referable to these areas are common.

Constitutional symptoms such as anorexia, weight loss, weakness, and fatigue are common.

Physical findings include peripheral adenopathy, pleural effusions, ascites, and hepatomegaly.

Pathologic evaluation

Optimal pathologic evaluation is critical in the evaluation of patients with carcinoma of an unknown primary site and can aid with the following:

• distinguishing carcinoma from other cancer types

• determining histologic type

• identifying the primary site

• identifying specific characteristics that may direct specific treatments.

Initial approach Although cytologic evaluation, including fine-needle aspiration biopsy, can often determine whether a lesion is malignant, a tissue biopsy will probably be needed to further evaluate the neoplasm. Tissue is required for paraffin-section immunohistochemistry, which is currently the usual methodology of choice in the work-up. Electron microscopy, which optimally requires glutaraldehyde fixation, is usually no longer required. Nucleic acid microarray analysis represents a technology of the future.

Carcinoma vs other neoplasms It is important to rule out the possibility of malignant lymphoma, malignant melanoma, and sarcoma. A battery of antibodies is utilized in an attempt to distinguish carcinoma from other types of neoplasms, as summarized in Table 1. The staining result obtained with any single marker is unreliable, as exceptions may occur for each individual antibody. For example, although keratin is a relatively reliable marker of carcinoma, some carcinomas (eg, adrenal cortical carcinoma or undifferentiated carcinoma of the thyroid) may be keratin-negative, whereas some types of sarcoma are characteristically keratin-positive (eg, epithelioid sarcoma).

Determination of histologic type There may be clues on initial histologic examination. For example, the presence of gland formation or mucin production would indicate an adenocarcinoma, whereas the presence of keratinization would indicate a squamous cell carcinoma. Evidence of neuroendocrine differentiation may be suggested by the presence of a characteristic relatively fine chromatin pattern. Immunohistochemistry can also be of use, as expression of keratin subtypes 7 and 20 would favor adenocarcinoma, and expression of keratin subtypes 5/6 and 14 would favor squamous cell carcinoma. Reliable neuroendocrine markers include chromogranin A and synaptophysin.

Identification of specific treatment target characteristics Even if the primary site is not determined, characteristics of the carcinoma may suggest specific treatment options or impart prognostic information. Examples of the former may include determination of estrogen or progesterone receptors or expression of members of the epidermal growth factor receptor family (eg, HER2/neu). Examples of the latter may include Ki-67, which is a surrogate marker of the proliferation rate of a neoplasm.

Clinical evaluation

After a biopsy has established metastatic carcinoma, a relatively limited clinical evaluation is indicated to search for a primary site. Recommended evaluation includes a complete history, physical examination, chemistry profile, CBC, chest radiograph, and CT scan of the abdomen.

Symptomatic areas Specific radiologic and/or endoscopic evaluation of symptomatic areas should be pursued. In addition, mammography, ultrasonography, and breast MRI should be performed in women with clinical features suggestive of metastatic breast cancer (eg, estrogen receptor-positive tumor and/or specific metastatic involvement including axillary nodes, bones, or pleura), and serum prostate-specific antigen (PSA) level should be measured in men with features suggestive of prostate cancer (eg, blastic bone metastasis; Table 2). In young men with poorly differentiated carcinoma, serum human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) levels should always be measured.

Asymptomatic areas In general, radiologic or endoscopic evaluation of asymptomatic areas is not productive and should be avoided. An exception is positron emission tomography (PET) scanning, which detects a primary site in almost 40% of cases and frequently changes the approach to treatment. The PET scan is now considered a standard part of the initial evaluation of patients with carcinoma of an unknown primary site.