[MOL] CUP Series Part 1 [03322] Medicine On Line

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[MOL] CUP Series Part 1


Carcinoma of unknown primary site is a common clinical syndrome and accounts for 3%-5 % of all cancer diagnoses. In addition to physical examination, routine laboratory tests, and chest radiograph, patient work-up should include computerized tomography of the abdomen and directed evaluation based upon signs and symptoms. Routine radiographic or endoscopic evaluation of asymptomatic areas is unrewarding. A number of patient subsets with specific treatment implications can be identified on the basis of clinical and pathologic features. Identification and treatment of these subsets (totaling approximately 40% of all patients with unknown primary tumors) is detailed in this article. For the remainder of patients, empiric chemotherapy is indicated unless performance status is poor. Recent experience with taxane-containing regimens suggests higher response rates and modest prolongation of survival. Ongoing trials are evaluating other new antineoplastic agents, in hopes of further improving therapy.
Cancer of unknown primary site is a common clinical syndrome, accounting for approximately 5% of all cancer diagnoses. Patients usually arrive at medical attention due to systemic symptoms or specific symptoms resulting from one or more sites of metastatic involvement; they should be considered to have cancer of unknown primary site after standard evaluation fails to identify the primary tumor site. Since most patients with cancer of unknown primary site have epithelial malignancy, the incidence of this syndrome increases with age, and the most common histologic diagnosis is adenocarcinoma.

Although this syndrome is relatively common, little attention has been given to improving therapy. This results in part from widespread nihilism regarding the prognosis of these patients. In addition, early attempts at systemic therapy yielded low response rates and had negligible effect on survival. However, it is now clear that this is a heterogeneous group of patients, and contains subsets of patients who benefit from specific treatment. Many of these patients can be identified using clinical and pathologic criteria, and require specific therapy. In the remaining patients who do not fit into any specific "treatable subset," recent empiric therapies incorporating new chemotherapeutic agents have yielded encouraging results, with early reports indicating higher response rates and improved survival.

In this review, the recommended clinical and pathologic evaluation of the patient with cancer of unknown primary site is detailed. Recommended treatment of specific subsets, as well as the evolving role of empiric treatment for patients who do not fit into any specific subset, are also discussed.

Initial Diagnosis and Staging

The typical patient with cancer of unknown primary site develops symptoms at a metastatic site, and comes to the attention of the medical oncologist after a biopsy has established a diagnosis of metastatic cancer. All patients presenting with metastatic carcinoma of unknown primary site should have a limited routine workup including a thorough history, physical examination, complete blood counts, chemistry profile, and chest radiograph. Localized symptoms should be evaluated by directed radiologic or endoscopic procedures. In addition, computerized tomography of the abdomen can identify a primary site in 10% to 35% of patients, and is frequently useful in identifying additional sites of metastatic disease.[1,2]

Diagnostic Evaluation -- Generalized Approach

Although overlap exists, subsequent clinical evaluation and treatment is dictated by the results of the initial light microscopic diagnosis. The four common histologic diagnoses are: adenocarcinoma (70%), poorly differentiated carcinoma (20%), squamous carcinoma (10%), and poorly differentiated neoplasm (5%).[3] Each of these four initial diagnoses requires slightly different clinical and pathologic evaluations.

If the histologic diagnosis is adenocarcinoma or poorly differentiated carcinoma, additional diagnostic tests should be performed in certain subsets. Men with bone metastases should have serum prostate specific antigen (PSA) levels measured.[4] Women with clinical presentations compatible with metastatic breast cancer should have mammography performed. Men who are less than 50 years old with poorly differentiated carcinoma should have measurement of serum human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) levels. If the tumor is located in the mediastinum, retroperitoneum, or lymph nodes, measurement of these serum tumor markers should be considered in men older than 50 with poorly differentiated carcinoma, but the clinical utility in this group is still controversial.[4] In patients with squamous carcinoma, additional evaluation is often necessary. Metastatic squamous cancer is most commonly found in cervical lymph nodes. In these patients, a primary site in the head and neck region is most probable, and direct endoscopic visualization of the entire area (oropharynx, nasopharynx, hypopharynx, larynx) reveals a primary site in the majority. In patients who have squamous cancer metastatic to inguinal lymph nodes, careful evaluation of the perineal areas (cervix, vagina, vulva, anus, rectum, penis) is required.

What Not To Do

Extensive radiologic evaluation of asymptomatic areas is rarely useful in identifying a primary site, and often results in confusing or false-positive information.[5] Endoscopy of the gastrointestinal tract is also of low yield in asymptomatic patients, although small, occult primary sites are occasionally identified.[5] These expensive tests should therefore be avoided in asymptomatic patients. Similarly, routine tumor markers (CEA, CA19-9, CA125, CA27-29) are non-specific and should not be used to infer a primary site in this patient group. If no primary site is identified by the above clinical evaluation, the clinician should avoid the temptation to "guess" at a primary site based on a suggestive clinical presentation. Rather, the patient should be treated using guidelines for carcinoma of unknown primary site.