INTRODUCTION  Cancer of unknown primary site (CUP) is a common clinical entity, accounting for 2 percent of all cancer diagnoses in the Surveillance, Epidemiology, and End Results (SEER) registries between 1973 and 1987 . Within this category, tumors from many primary sites with varying biologies are represented; this heterogeneity has made the design of therapeutic studies difficult.

Substantial improvements have been made in the management and treatment of some patients with CUP. The identification of specific subgroups of treatable patients has been made possible by the development of specialized immunohistologic techniques that can aid in tumor characterization, and by the recognition of several clinical syndromes that permit prediction of chemotherapy responsiveness.

The typical patient with CUP presents with symptoms referable to a metastatic site. The initial work-up, including physical examination, laboratory and radiographic study, fails to identify the primary site. Light microscopic evaluation of biopsy material places the tumor into one of five histologic categories, which then guides further evaluation:

• Adenocarcinoma approximately 70 percent

• Poorly differentiated carcinoma  15 to 20 percent; an additional 10 percent represent poorly differentiated adenocarcinoma

• Poorly differentiated neoplasm  less than 5 percent

• Squamous cell carcinoma (SCC)  SCC is uncommon in the absence of an obvious primary unless patients present with a neck mass (See "Squamous cell carcinoma of unknown primary site")

• Neuroendocrine carcinoma  uncommon. This group includes patients with either neuroendocrine carcinoma identified histologically (eg carcinoid, small cell neuroendocrine carcinoma) or poorly differentiated carcinoma with neuroendocrine features by immunohistochemical staining.

These histologically defined subgroups vary with respect to clinical characteristics, diagnostic approach, treatment, and prognosis. An overview of these issues is presented here. Each of the five subgroups is discussed separately in more detail. (See specific topic reviews).

DIAGNOSIS  The likelihood of determining the primary site depends upon the histologic category and the site of presentation. The initial work-up of patients presenting with a presumed CUP should not be exhaustive, and should instead be geared toward evaluation of likely primary sites. This initial evaluation should include, at a minimum, a thorough history and physical examination (including a pelvic examination in women and a prostate examination in men), complete blood count, urinalysis, multichannel chemistries, a chest radiograph, and computed tomography (CT) of the abdomen and pelvis. The choice of further diagnostic procedures that are likely to yield an improved level of diagnosis varies with the subgroups.

Neoplasms of unknown primary site  The designation neoplasm of unknown primary site implies that the pathologist, although confident of the diagnosis of malignancy, is unable on light microscopy to distinguish between a carcinoma, sarcoma, or a hematologic neoplasm. However, a more precise diagnosis is essential since therapy for these tumors is quite different, and may be potentially curative in some.

The use of immunohistochemistry, electron microscopy, and chromosomal analysis may permit the identification of most neoplasms of unknown primary site as carcinomas, sarcomas, or lymphomas. (See "Poorly differentiated neoplasms of unknown primary site").

• Immunohistochemistry  An initial panel of immunohistochemical stains utilizing antibodies to vimentin, cytokeratin, carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), and leukocyte common antigen (LCA, CD45), among others, should be performed on the tissue block. The LCA stain usually can make the distinction between lymphoma and carcinoma, while vimentin is frequently expressed in sarcomas.

• Transmission electron microscopy  Electron microscopy (EM) is extremely reliable in distinguishing lymphoma from carcinoma and is probably superior to immunohistochemistry in the identification of poorly differentiated sarcomas, melanomas, and neuroendocrine tumors. EM can also assist in the distinction between adenocarcinoma and squamous cell carcinoma if light microscopy is not definitive.

• Genetic analysis  Chromosomal analysis of fresh tissue is useful in the recognition of non-Hodgkin's lymphomas, some sarcomas, and some testicular and extragonadal germ cell tumors in men .

Non-Hodgkin's lymphomas account for 35 to 65 percent of poorly differentiated neoplasms of unknown primary site. Most of the remaining tumors are carcinomas.

Poorly differentiated carcinoma of unknown primary site  These patients have a high frequency of mediastinal and retroperitoneal involvement. For this reason, chest and abdominal CT scans should be routinely performed during the initial work-up. Elevated serum concentrations of human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) may suggest the diagnosis of extragonadal germ cell tumor of unknown primary site.

The results of immunohistochemical staining of biopsy material assist in the identification of specific tumors. Although the diagnostic yield is considerably less than in patients with neoplasms of unknown primary site, treatable tumors from unsuspected primary sites can be identified in 10 to 20 percent

Adenocarcinoma  The clinical presentation of adenocarcinoma of unknown primary site is dictated by the sites of tumor involvement, which frequently include the liver, lungs, lymph nodes, and bones. The primary site is identified either initially or on further testing in only 15 to 20 percent of patients antemortem  . In autopsy series, the most common identified primary sites were the pancreas, hepatobiliary tree, and lung, together accounting for approximately 40 to 50 percent of cases  . Tumors may arise from other gastrointestinal sites, and a wide variety of other primary sites are occasionally encountered. Adenocarcinomas from the breast and prostate are relatively infrequent in this group of patients, despite being the most common cancer types in women and men, respectively

Initial studies should focus on determining the extent of metastatic disease. A specific primary site is suggested by abdominal CT in 10 to 35 percent of patients . Positron emission tomography (PET) is also a useful procedure, and results in the identification of a primary site in 20 to 30 percent of patients . All men should have a serum PSA determination, and mammography should be considered in women with a clinical presentation compatible with metastatic breast cancer. Tumors can also be stained immunohistochemically to detect the presence of PSA in men, and the expression of estrogen or progesterone receptors in women.

In an effort to identify the primary site, additional signs or symptoms, such as hemoccult-positive stool, should be evaluated with appropriate radiographic or endoscopic studies. Extensive radiologic evaluation of asymptomatic areas is rarely useful in identifying a primary site, and often results in confusing or false-positive information. Endoscopic evaluation of the upper and/or lower gastrointestinal tract is of low yield in asymptomatic patients, although small, occult primary sites are occasionally identified.

Common tumor markers (CEA, CA 19-9, CA 15-3, CA-125) are not generally useful as diagnostic or prognostic tests; however, some are frequently elevated in the serum of patients with adenocarcinoma of unknown primary site, and serial measurement may be useful in following the response to therapy for individual tumors.

Squamous cell carcinoma  Immunohistochemical studies and EM are of little value in identifying the primary site for patients with squamous cell carcinoma of unknown primary site. The diagnostic evaluation of such patients is dependent upon the predominant area of the metastasis. (See "Squamous cell carcinoma of unknown primary site").

• Inguinal adenopathy  Most patients with SCC involving inguinal nodes have a detectable primary site in the genital or anorectal area. In women, careful examination of the vulva, vagina, and cervix is important; careful inspection of the penis should be performed in men. Digital rectal examination and anoscopy should be performed in both sexes.

• Upper and mid cervical adenopathy  Upper and mid cervical adenopathy is most often due to head and neck cancer and requires further evaluation with CT of the head and neck, direct laryngoscopy, and nasopharyngoscopy. PET scanning should be performed if a primary site is not identified by CT scanning or endoscopy.

• Adenopathy at other sites  Lower cervical or supraclavicular adenopathy, or metastases at sites other than cervical and inguinal nodes, usually represents metastasis from a primary lung cancer; these patients should be evaluated with CT of the chest and fiberoptic bronchoscopy.

Neuroendocrine tumors  There are three types of neuroendocrine tumors that can present as a tumor with an unknown primary site.

• Low grade neuroendocrine carcinoma  Metastatic carcinoid or islet cell tumors occasionally present without an obvious primary site, usually metastatic to the liver. Primary sites are subsequently found within the intestine or pancreas in some patients.

• Small cell carcinoma  Most patients who present with metastatic small cell anaplastic carcinoma have a bronchogenic malignancy. CT of the chest and fiberoptic bronchoscopy usually identifies the primary site. Other potential primary sites include the salivary gland, esophagus, bladder, ovary, prostate, and cervix. The choice of diagnostic study is dictated by localizing symptoms.

• Poorly differentiated neuroendocrine carcinoma  This designation is applied to poorly differentiated carcinomas that exhibit neuroendocrine features on electron microscopy or immunohistochemistry, but are not sufficiently differentiated to suggest the diagnosis of a small cell bronchogenic cancer or a carcinoid/islet cell tumor. Most patients with this diagnosis have clinical evidence of a high grade or aggressive malignancy, usually with metastases in multiple sites [13] . Lymph nodes in the retroperitoneum and mediastinum are frequently involved. A specific primary site is rarely identified, even with extensive testing.

TREATMENT  If a primary site is strongly suggested, treatment is selected based upon the usual treatment for advanced cancer arising from that site. While regional disease is amenable to surgery and/or radiation therapy, multimodality treatment should be considered for disseminated disease.

• Subsets of patients with the most favorable prognosis include those with an identified non-Hodgkin's lymphoma, Hodgkin's lymphoma, germ cell tumor, or thyroid cancer. These patients are treated according to guidelines for these specific neoplasms.

• A fair response to combination therapy can be expected for tumors thought to arise in the breast, ovary, and prostate, while metastatic gastrointestinal or urogenital tumors remain difficult to treat.

Some other malignancies that have no obvious primary site are treatable and potentially curable. The following subsets of patients respond to specific forms of chemotherapy

• Poorly differentiated carcinoma with clinical features of extragonadal germ cell malignancies, which is treated as a nonseminomatous extragonadal germ cell malignancy.

• Squamous cell carcinoma metastatic to cervical lymph nodes, which is treated as advanced head and neck cancer.

• Metastatic adenocarcinoma involving only axillary lymph nodes in women, which is treated as stage II breast cancer.

• Peritoneal carcinomatosis in women, which is treated as advanced ovarian cancer.

• Poorly differentiated neuroendocrine carcinoma, which is treated similar to small cell lung cancer.

In addition, men with osteoblastic metastases, high serum PSA levels, or tumors that stain for PSA immunohistochemically, are treated as stage IV prostate adenocarcinoma.

In most cases, however, it is not possible to identify the primary site, and the patient does not fall into one of the above subgroups. Current empiric chemotherapy regimens have improved the treatment results for this group of patients, and now result in median and two-year survivals of 10 to 12 months and 20 to 25 percent, respectively