The typical patient with adenocarcinoma of unknown primary site develops symptoms at a metastatic site, but routine history, physical examination, chest radiography, and laboratory studies fail to identify the primary site. Biopsy of a metastatic lesion establishes the diagnosis. In most patients, metastases are present at more than one visceral site; frequent metastatic sites include the liver, lungs, lymph nodes, and bones. The incidence of adenocarcinoma of unknown primary site increases with age.

The clinical course of patients with adenocarcinoma of unknown primary site is usually dominated by symptoms related to the sites of metastases. During the clinical course, the primary site becomes obvious in only 15% to 20% of patients (3). Many patients have widespread metastases and poor performance status at the time of diagnosis; outlook for most of these patients is poor, with median survival of 6 months. However, subsets of patients with much more favorable outlooks are contained within this large group, and optimal initial evaluation enables the identification of these treatable subsets. In addition, empiric chemotherapy incorporating newer agents has produced higher response rates and probably improved survival of patients with good performance status.

The light microscopic diagnosis of adenocarcinoma is usually made without difficulty based on the formation of glandular structures of neoplastic cells. Features of adenocarcinoma can be reliably recognized by examining small tissue samples or even by cytology; therefore, fine-needle aspiration biopsy is a reliable diagnostic test in this subset of unknown primary cancer patients. Unfortunately, most adenocarcinomas share common histologic features so examination of tissue from a metastatic site cannot lead to reliable diagnosis of the primary. Several histologic features are especially common in patients with various gastrointestinal primaries; these include well-differentiated glandular structure, signet ring formations, and evidence of mucin production. However, even these features are not specific enough to define a primary site.

Immunoperoxidase stains are also of limited utility in identifying the site of origin of most adenocarcinomas. Positive staining for prostate-specific antigen (PSA) is an exception, reliably identifying the prostate as a site of origin. Immunoperoxidase staining for estrogen receptor and/or progesterone receptor suggest metastatic breast cancer in women with metastatic adenocarcinoma. Other immunoperoxidase stains, particularly the differential expression of cytokeratin 7 versus cytokeratin 20, have been evaluated (4,5,6). In particular, the staining combination of positive cytokeratin 20/negative CK 7 occurs in approximately 80% of colon cancers (4). Although not specific to colon cancer (e.g., 15% of gastric cancers have similar staining), colonoscopy should be considered in the evaluation of patients with this staining pattern.

The diagnosis of poorly differentiated carcinoma implies the loss of some of the distinctive features of adenocarcinoma and provides the pathologist with even fewer clues as to the site of tumor origin. This diagnosis should be interpreted with caution because some of these patients may have unrecognized tumor types (e.g., poorly differentiated neuroendocrine carcinoma) with specific treatment implications. The diagnosis of poorly differentiated adenocarcinoma is usually made when only minimal glandular formation is seen in histologic examination. However, the diagnosis is sometimes made based on positive mucin staining, even when no glandular features are present on histologic examination. It is clear that adenocarcinoma, poorly differentiated adenocarcinoma, and poorly differentiated carcinoma are diagnoses representing parts of a spectrum of tumor differentiation rather than specific, sharply demarcated entities. Different pathologists may use slightly different criteria for making each of these three diagnoses. Therefore, additional immunoperoxidase staining is appropriate in most patients with the initial diagnosis of poorly differentiated adenocarcinoma to identify specific subtypes. At present, evaluation and treatment of patients with poorly differentiated adenocarcinoma should follow guidelines outlined for poorly differentiated carcinoma.

The identification of increasing numbers of oncoproteins that define the malignant phenotype and are prognostically important has become a primary focus in the characterization of tumors. Some of these substances (e.g., epidermal growth factor, vascular endothelial growth factor, HER-2) are now targets for novel therapeutic agents. A substantial percentage of unknown primary cancers are known to overexpress p53, Bcl-2, Cmyc, RAS, and EGFR (7,8). However, the value of these markers in predicting prognosis or determining therapy is currently undefined.

The development of molecular pathology techniques enabling genetic profiling of specific cancer types may greatly modify the approach to patients with adenocarcinoma of unknown primary site in the future. Characteristic gene expression profiles have already been identified for many solid tumor types. A number of studies have recently shown that accurate classification of solid tumor types can be made based on specific expression of a limited number of genes (9,10). With reduced numbers of genes involved, quantitative polymerase chain reaction techniques can be used rather than microarray, enabling testing in formalin-fixed, paraffinized tissue (11).

More recently, several different DNA microarray platforms have been tested for their ability to successfully identify cancer types. Using a platform containing 79 gene markers, Tothill et al. identified specimens (primary or metastatic) from 14 known tumor types with 89% accuracy (12). Several gastrointestinal primary sites were included in this evaluation. In addition, a small group of specimens from patients with carcinoma of unknown primary site were tested. In 11 of 13 cases, the primary site was predicted with high confidence; in most cases, the predicted primary site was compatible with clinical features of the patient.

At present, several studies are ongoing to validate the ability of various microarray platforms to reliably identify primary sites in patients with carcinoma of unknown primary site. If predicted primary sites reliably correlate with suggestive clinical features, response to treatment, and observed tumor biology, these procedures will become vital diagnostic tools and will greatly reduce the number of patients with the final diagnosis of carcinoma of unknown primary site.

If a primary site is not evident in a patient with metastatic cancer after a basic evaluation (history, physical examination, complete blood counts, biochemistry profile, urinalysis, and chest radiography), several additional tests should be performed. All men should have a serum PSA determination, and women with clinical presentation compatible with metastatic breast cancer should undergo mammography because specific palliative therapy is available for patients with advanced prostate or breast cancer. CT of the abdomen should be performed in all patients because primary sites are identified in 10% to 35% of patients, and additional metastatic sites are often recognized (13,14). Positron emission tomography (PET) identifies a primary site in up to 30% of patients and is therefore a useful diagnostic procedure (15,16). Additional signs or symptoms should be evaluated with appropriate radiologic studies.

In patients who have no primary site identified after the previous diagnostic procedures are completed, further evaluation is extremely unlikely to demonstrate a primary site. In general, extensive radiologic evaluation of asymptomatic areas and routine gastrointestinal endoscopy should be avoided. However, the yield of endoscopy may be somewhat higher in patients with intra-abdominal presentations (e.g., predominant liver metastases, peritoneal carcinomatosis), particularly if histologic features are suggestive of a gastrointestinal primary site. In this relatively select group of patients, endoscopic evaluation of the gastrointestinal tract should be considered.

Commonly used serum tumor markers, including carcinoembryonic antigen, cancer antigen (CA) 19-9, CA 15-3, CA 125, human chorionic gonadotropin, and alpha-fetoprotein are frequently elevated in patients with carcinoma of unknown primary site. However, these markers are nonspecific and are rarely useful in defining a primary site (17,18). However, elevated serum tumor markers are frequently useful in monitoring response to therapy.

Adenocarcinoma with predominant or exclusive involvement of the peritoneal surface is more common in women than in men. Most women presenting with this syndrome have an easily identifiable primary tumor in the ovary, although occasionally cancer arising in the breast or gastrointestinal tract can present in this manner. Women who develop peritoneal carcinomatosis in the absence of an identifiable primary site should always be approached as if they had ovarian cancer. This syndrome can develop in women with normal ovaries or a history of previous oophorectomy, and occurs with increased incidence in women with BRCA-1 mutations (19,20). Many women with this syndrome have histologic features typical of ovarian carcinoma, such as papillary configuration or psammoma bodies. Serum CA 125 levels are usually elevated. When histologic features suggest ovarian carcinoma, this syndrome has been termed “peritoneal papillary serous carcinoma” or “multifocal extraovarian serous carcinoma.”

Women with this syndrome often respond well to the chemotherapy regimens effective in the treatment of advanced ovarian carcinoma (Table 52.1). Initial response rates are high, and long-term remissions occur in 15% to 20% of patients (21,22,23,24,25,26). Recent reports have documented the activity of platinum/paclitaxel regimens, as used in patients with advanced
ovarian carcinoma (27). Most long-term remissions have been observed in patients who undergo successful surgical cytoreduction prior to the administration of chemotherapy.

The peritoneal epithelium is now accepted as a site of origin for some of the women with these carcinomas. The contiguity of the peritoneal and ovarian epithelial surfaces may explain the similar biology of these two tumor types. In fact, these tumors are now believed to be similar enough that women with peritoneal papillary serous carcinoma are routinely included in clinical trials for stage III ovarian carcinoma. At present, optimal management for women with this syndrome should include initial maximal surgical cytoreduction followed by taxane/platinum chemotherapy (27,28). For women with minimal residual disease after surgical cytoreduction, intraperitoneal chemotherapy may also play a role in treatment (29).

Most men presenting with peritoneal carcinomatosis do not have tumors that are highly responsive to chemotherapy. Presumably, most men with this syndrome have occult tumors of gastrointestinal primary origin. Occasional men have been reported with papillary adenocarcinoma and elevated serum CA125 levels (30). In these men, a trial of a taxane/platinum-based regimen, as used for ovarian cancer, seems reasonable. For other men presenting with peritoneal carcinomatosis, a trial of empiric chemotherapy for adenocarcinoma of unknown primary site should be considered. In addition, women with this syndrome who do not respond promptly to a taxane/platinum-based regimen are likely to have occult gastrointestinal primary sites, and a second-line empiric regimen effective in the treatment of gastrointestinal malignancies should be considered. Primary peritoneal mesothelioma is also a diagnostic consideration in these patients and is discussed in detail in Chapter 53.

Occasionally, only a single metastatic lesion can be identified after a complete staging evaluation. Such single lesions have been described in a wide variety of sites, including lymph nodes, liver, brain, lung, adrenal gland, bone, and subcutaneous tissue. The possibility of a primary tumor in an unusual site (rather than a metastasis) should always be considered in such situations, but this possibility can usually be excluded on the basis of clinical or pathological features.

In most of these patients, other metastatic sites are recognized within a relatively short time. However, some patients have prolonged diseasefree intervals following effective local therapy of a single metastatic lesion. Prior to initiating local treatment, a PET scan is useful to rule out the presence of other unsuspected metastatic sites (31). If no other metastases are detectable, definitive local therapy of the solitary lesion should proceed. In most instances, surgical resection is preferable if technically feasible. Occasional patients with long-term survival following definitive treatment of a single “metastatic” lesion have been described (32). The role of systemic chemotherapy in addition to definitive local therapy is undefined; however, patients with poorly differentiated adenocarcinoma may benefit from empiric platinum-based therapy.

The most common gastrointestinal presentation with a single lesion involves a single liver lesion. Distinction between a primary hepatoma or hepatobiliary carcinoma versus a metastatic lesion is sometimes problematic. However, histologic features and/or specialized immunohistochemical staining are usually successful in identifying hepatobiliary origin. Immunoperoxidase staining patterns typical for hepatobiliary tumors include positive alpha-fetoprotein, polyclonal but not monoclonal carcinoembryonic antigen, and loss of reticulin staining. In patients who are surgical candidates, hepatic resection should be considered. In patients who are not surgical candidates but have tumor diameter ≤5 cm, radiofrequency ablation can provide excellent local control (see Chapter 33 for a detailed discussion of ablative techniques) (33). Other local therapies (e.g., stereotactic radiation, chemoembolization) may also be useful in selected patients. Patients with inadequate local control after attempted local therapy or those who develop additional metastases should be considered for empiric chemotherapy.

Metastatic breast cancer should be suspected in women who have axillary lymph node involvement with adenocarcinoma. Initial lymph node biopsy should include measurement of estrogen/progesterone receptors and HER-2 oncoprotein; elevated levels provide strong evidence for the diagnosis of breast cancer (34). Breast MRI scanning and PET scanning may identify a breast primary site even when mammography is normal (35,36). Women with metastases isolated to ipsilateral lymph nodes after complete evaluation should be managed according to guidelines for stage II breast cancer, whereas women with additional metastatic sites should receive treatment effective for metastatic breast cancer. Gastrointestinal tumor origin is
usually not a clinical suspicion in this patient group; further discussion of management of these patients can be found elsewhere.

Metastatic prostate carcinoma should be suspected in men with adenocarcinoma predominantly involving bone, particularly if the metastases are blastic. Elevated serum levels of PSA or tumor staining with PSA provides confirmatory evidence of prostate cancer. Treatment of these patients should follow guidelines for advanced prostate cancer. Occasionally, patients have been reported with clinical presentations atypical for prostate cancer, in whom the diagnosis was supported only by elevation of serum PSA (37,38). Most of these patients had adenopathy (retroperitoneal, mediastinal) or lung metastases; other intra-abdominal presentations are extremely rare.