Carcinoma of Unknown Primary Site

Carcinoma of 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 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 unknown primary site have advanced, metastatic cancer, 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 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 lung was the most common primary site, while 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.

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

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

Common physical findings Findings on physical examination are also frequently abnormal; common anomalies include peripheral adenopathy, pleural effusions, ascites, and hepatomegaly.

Pathologic evaluation

Optimal pathologic evaluation is critical in the initial evaluation of patients with carcinoma of unknown primary site, and can accomplish the following:

The initial light microscopic examination can separate patients into four categories: adenocarcinoma (65%), squamous cell carcinoma (10%), poorly differentiated carcinoma or poorly differentiated adenocarcinoma (20%), and poorly differentiated neoplasm (5%). These categories can be used to guide further evaluation.

Adenocarcinoma In general, additional pathologic study in patients with adenocarcinoma is unlikely to identify the primary site definitively. An exception is adenocarcinoma of the prostate, in which positive tissue staining for prostate-specific antigen (PSA) is quite specific. Other light microscopic features of adenocarcinoma, such as signet-ring cell formations and papillary features, are nonspecific and should not be used to infer a primary site.

Poorly differentiated carcinoma All patients with the light microscopic diagnosis of poorly differentiated carcinoma or poorly differentiated neoplasm require additional specialized pathologic evaluation. Often, a surgical biopsy rather than a needle aspiration biopsy is necessary for optimal evaluation of these patients.

All poorly differentiated carcinomas of unknown primary site should be studied further with specific immunoperoxidase stains. Anaplastic lymphoma can be reliably diagnosed with the leukocyte common antigen (LCA) stain. Other tumor types (eg, melanoma, sarcoma, neuroendocrine carcinoma) can be suggested by specific immunoperoxidase staining features. Immunoperoxidase stains useful in the evaluation of poorly differentiated neoplasms of unknown primary site are listed in Table 1.

If the identity of poorly differentiated neoplasms is not established after immunoperoxidase staining, electron microscopy should be considered. Rebiopsy to obtain appropriate tissue should be considered in young patients with poorly differentiated neoplasm, since specific ultrastructural findings can result in the diagnosis of various poorly differentiated sarcomas, poorly differentiated neuroendocrine tumors, aggressive lymphoma, or melanoma.

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.

Evaluation of symptomatic areas In addition, specific radiologic and/or endoscopic evaluation of symptomatic areas should be pursued. For example, mammograms should be performed in women with clinical features suggestive of metastatic breast cancer (eg, axillary adenopathy), and serum PSA level should be measured in men with features suggestive of prostate cancer (eg, blastic bone metastasis). In young men with poorly differentiated carcinoma, serum human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) levels should always be measured.

Evaluation of asymptomatic areas In general, radiologic or endoscopic evaluation of asymptomatic areas is not productive and should be avoided. In one small series, positron emission tomography (PET) scanning detected primary sites in 7 of 29 patients (24%); further experience is necessary before recommending this procedure routinely. Several reports have documented that superfluous testing is frequently performed in these patients, and several thousand dollars can be spent in a futile search for the primary tumor site.

Patients with cervical lymphadenopathy Metastatic squamous carcinoma in cervical lymph nodes usually involves upper or mid-cervical locations. All patients should undergo a thorough search for a primary site in the head and neck region, including direct endoscopic examination of the oropharynx, hypopharynx, nasopharynx, larynx, and upper esophagus. Biopsy of any suspicious areas should be taken. Fiberoptic bronchoscopy should be considered in patients with involvement of low cervical or supraclavicular nodes. This type of evaluation will identify a primary site, usually in the head and neck, in 85%-90% of these patients.

Patients with inguinal lymphadenopathy Patients with metastatic squamous cell cancer presenting in inguinal lymph nodes almost always have an identifiable primary site in the perineal area. Women should undergo careful examination of the vulva, vagina, and cervix; men should have careful inspection of the penis. Anoscopy should be performed to exclude lesions in the anorectal area.

Treatment

Table 2 summarizes the recommended treatments for various recognized clinicopathologic subsets.

When evaluating patients with adenocarcinoma of unknown primary site, several clinical subsets should be identified and treated specifically. Empiric therapy for patients not included in any of these subsets is outlined in the final section of this chapter.

Women with isolated axillary adenopathy Treatment appropriate for stage II breast cancer should be administered. Mastectomy reveals an occult primary cancer in 50%-60% of these patients, even when physical examination and mammography are normal. Axillary dissection with breast irradiation is also a reasonable treatment, although there are no definitive comparisons of this approach with mastectomy. Adjuvant systemic therapy, following standard guidelines for stage II breast cancer, is also indicated.

Women with peritoneal carcinomatosis Often, the histopathology in these patients suggests ovarian cancer (ie, serous cystadenocarcinoma or papillary adenocarcinoma), and they should be treated as if they had stage III ovarian cancer. Initial cytoreductive surgery should be followed by chemotherapy with paclitaxel (Taxol) and a platinum compound, as recommended for advanced ovarian cancer. In these patients, serum CA-125 can often be used as a tumor marker.

Men with bone metastasis Metastatic prostate cancer should be suspected, and usually can be diagnosed with either elevated serum PSA or positive tumor staining for PSA. In such patients, hormonal therapy, as recommended for prostate cancer, is often of palliative benefit.

Patients with a single metastatic site Local treatment, either with surgical excision or radiation therapy, should be administered to the patient who presents with clinical evidence of a single metastasis. Some of these patients have prolonged survival after local therapy, particularly those who present with a sole metastasis in an isolated peripheral lymph node group. The role of "adjuvant" systemic therapy is undetermined in these patients.

Squamous cell cancer accounts for only 10% of light microscopic diagnoses in patients with unknown primary cancer. Isolated cervical adenopathy is the most common presentation for squamous carcinoma of unknown primary site; an additional group of patients have isolated inguinal adenopathy at presentation. Specific management is essential for both of these subgroups, since both have the potential for long-term survival following treatment.

Patients with cervical lymphadenopathy in whom no primary site is identified should be treated as if they had a primary site in the head and neck. Local treatment should include either radiation therapy or modified radical neck dissection followed by radiation. Radiation therapy doses and techniques should be identical to those used in treating patients with known head and neck primaries. In addition to the involved neck, the nasopharynx, oropharynx, and hypopharynx should be included in the radiation portal. Recent clinical trials have documented the additional benefit of chemotherapy, administered concurrently with radiation therapy or prior to surgical treatment.

Five-year survival rates of 30%-70% have been reported, with the size and extent of cervical node involvement being the most important determinants of prognosis.

Patients with inguinal lymphadenopathy Identification of a primary site in the perineal area is important in patients with inguinal lymphadenopathy, as curative therapy is available for some patients even after metastasis to inguinal lymph nodes. In the uncommon patient in whom no primary site is identified, inguinal node dissection, with or without radiation therapy, can result in long-term survival. While limited data exist in this uncomon subgroup, the demonstrated superiority of combined modality therapy vs local treatment alone for primary squamous cancers in the perineal area (eg, cervix, anus) has led to a suggestion that the addition of platinum-based chemotherapy may improve treatment results.

This heterogeneous group includes a minority of patients with highly responsive neoplasms, and therefore requires special attention in initial clinical and pathologic evaluation. Specialized pathologic techniques can identify some patients with tumor types known to be treatable; these patients should be treated using standard guidelines for the appropriate tumor type.

In the remaining patients, several investigators have documented an increased responsiveness to platinum-based chemotherapy when compared with patients with adenocarcinoma of unknown primary site. In addition, several series have described a small cohort of long-term survivors following platinum-based treatment. Patients with poorly differentiated adenocarcinoma have usually been included in this group when making treatment decisions. Although most patients in this group should receive an empiric trial of treatment, several specific subsets can be recognized.

Extragonadal germ-cell cancer syndrome Young men with predominant tumor location in the mediastinum and retroperitoneum and/or high levels of serum HCG or AFP should be treated as if they had a poor prognosis germ-cell tumor.

Molecular genetic analysis can identify an i(12p) chromosomal abnormality diagnostic of a germ-cell tumor in some of these patients, even when the diagnosis cannot be made by any other pathologic evaluation. Patients with germ-cell tumors diagnosed in this manner have been shown to be as responsive to treatment as patients with extragonadal germ-cell tumors of typical histology.

Poorly differentiated neuroendocrine carcinoma With the improved immunoperoxidase stains now available, neuroendocrine features are recognized more frequently in patients with poorly differentiated carcinoma. These tumors are distinct in biology and therapeutic implications from well-differentiated neuroendocrine tumors (eg, carcinoid tumors, islet-cell tumors) of unknown primary site, which almost always present with multiple liver metastases. In contrast to typical carcinoid tumors, poorly differentiated neuroendocrine tumors are difficult to recognize by light microscopic examination alone, although some of the latter tumors have neuroendocrine or "small-cell" features.

Patients with poorly differentiated neuroendocrine carcinoma of unknown primary site should receive a trial of chemotherapy with a regimen containing a platinum and etoposide. In a group of 51 such patients, the complete response rate was 28% following treatment with cisplatin (Platinol) and etoposide, with or without bleomycin (Blenoxane); overall response rate was 71%. Eight patients (16%) had durable complete remissions.

More recently, the combination of paclitaxel, carboplatin (Paraplatin), and etoposide has shown a high level of efficacy in the treatment of poorly differentiated neuroendocrine tumors (see "Empiric chemotherapy" below) and is better tolerated than cisplatin/etoposide.

Although the identity of most poorly differentiated neuroendocrine tumors remains unknown, this group of chemotherapy-responsive patients can be reliably identified using specialized, but widely available, pathologic evaluation.

Other patients with poorly differentiated carcinoma Patients in this group should receive an empiric trial of chemotherapy, unless extremely poor performance status precludes this possibility. In a group of 220 such patients treated at a single institution with cisplatin-based regimens effective for germ cell tumors, the overall response rate was 64%, with 27% complete responses. Median survival of this group was 20 months, and 13% of patients have been disease-free for more than 8 years and are considered cured. Although the young median age of 39 years indicates that this was a selected patient group, the extreme chemosensitivity of some patients in this large, heterogeneous group is clearly demonstrated.

Predictors of responsiveness to chemotherapy Several clinical features predictive of tumor responsiveness to chemotherapy have been identified. These include:

However, complete responses and long-term survival are occasionally seen in patients with none of these favorable characteristics, so a brief trial of treatment should be considered in all patients with reasonable performance status.

Systemic therapy for patients not included in any specific treatable subgroup has been difficult. Unfortunately, this group includes the majority of patients with adenocarcinoma of unknown primary site; some patients with poorly differentiated carcinoma and no "favorable" clinical features also respond poorly to current therapy.

䭲ld?regimens Table 3 summarizes results compiled from phase II trials of empiric chemotherapy. Most patients in these trials had adenocarcinoma, but 5%-10% had poorly differentiated carcinoma. In general, the most extensively tested empiric regimens have been those effective for GI malignancy and breast cancer, as well as various cisplatin-based regimens. Most tested regimens have produced response rates of 20%-35%, and median survival durations of 5-8 months. There is little evidence for prolongation of median survival or long-term complete remissions with any of these regimens, and none is considered "standard treatment" in this group of patients.

Regimens incorporating new agents The recent availability of several new antineoplastic agents with broad-spectrum activity has renewed interest in the empiric therapy of carcinoma of unknown primary site. The taxanes, gemcitabine (Gemzar), and the topoisomerase I inhibitors are all agents with potential efficacy in the treatment of unknown primary cancer.

Results with taxane-based regimens are included in Table 3. Most experience with these regimens suggests higher response rates and longer median survivals than with older regimens. In addition, the toxicity of taxane/carboplatin regimens is reduced when compared to previous cisplatin-based regimens. Long-term follow-up of patients treated with paclitaxel/carboplatin/etoposide shows actual 2-year and 3-year survivals of 20% and 14%, respectively. At present, paclitaxel/carboplatin, with or without etoposide, should be considered for empiric therapy of patients with adenocarcinoma of unknown primary site and good performance status.

Carcinoma of Unknown Primary Site

Epidemiology

Signs and symptoms

Pathologic evaluation

Clinical evaluation

Treatment

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