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Management of Patients With Cancer of Unknown Primary Site

Management of Patients With Cancer of Unknown Primary Site

ABSTRACT: Cancer of unknown primary site represents approximately 3% to 5% of all new cancer diagnoses. Adenocarcinomas account for 60% of all unknown primary cancers and poorly differentiated carcinomas or adenocarcinomas, for 30%. Historically, the prognosis for most patients with unknown primary tumors has been poor, with survival often less than 6 months from diagnosis. Recent advances in diagnostic techniques, including immunocytochemical and molecular genetic methods, have increased the probability of identifying a likely underlying tumor type. Based on clinical and pathologic features, approximately 40% of patients can be categorized within subsets for which specific treatment has been defined. Empiric therapy is an option for the remaining 60% of patients. In these patients, favorable prognostic factors for treatment response include tumor location in lymph nodes, fewer sites of metastases, younger age, and poorly differentiated carcinoma histology. Although experience remains limited, the incorporation of a taxane into empiric regimens appears to improve response rates and survival. A recent study of paclitaxel (Taxol), carbo-platin (Paraplatin), and etoposide in 55 patients with cancer of unknown primary site reported an overall response rate of 47% and a median overall survival of 13.4 months. Investigations continue to explore new diagnostic techniques and novel therapeutic approaches. [ONCOLOGY 14(4);563-575, 2000]


Cancer of unknown primary site accounts for 3%
to 5% of all cancer diagnoses.[1] This syndrome occurs with equal
frequency in men and women and increases in incidence with advancing
age. Numerous clinical presentations and histologic tumor
characteristics are represented in this heterogeneous group of
patients. Common sites of metastases include the liver, bone, lung,
lymph nodes, pleura, and brain. The majority of patients have
metastases present in two or more sites.[2] Patients are diagnosed
with cancer of unknown primary site after an initial standard
evaluation fails to identify a primary tumor site.

Historically, patients with an unknown primary tumor have responded
poorly to empiric therapy, and median survival from diagnosis has
usually been less than 8 months. The limited activity of early
chemotherapeutic regimens and short median survival have contributed
to clinical nihilism about patients with cancer of unknown primary site.

A number of patient subsets with specific treatment implications have
now been described, however. These subsets, identified by specific
clinical or pathologic criteria, account for approximately 40% of all
patients with unknown primary tumors. In the remaining patients,
recent studies of empiric taxane-containing therapies have produced
higher response rates, and have probably extended survival. Ongoing
evaluations of other new regimens and approaches to the treatment of
cancer of unknown primary may result in additional treatment advances.

Diagnosis and Evaluation

Approximately 60% of patients with cancer of unknown primary site
have well-differentiated or moderately well-differentiated
adenocarcinoma. Poorly differentiated carcinomas or poorly
differentiated adenocarcinomas are diagnosed in approximately 30% of
patients. Squamous cell carcinomas and poorly differentiated
neoplasms account for 5% of diagnoses. Clinical presentation,
evaluation, prognosis, and treatment options differ for these four
histologically distinct groups. The presence of specific clinical
features or the use of specialized pathologic studies can identify
subsets within these broad categories of patients who may benefit
from tumor-specific therapy.

Clinical Evaluation

In most patients, the clinical evaluation, including the search for
the primary site, should be brief and focused. A careful history
should be taken and a complete physical examination should be
performed (including pelvic and rectal examinations), with routine
laboratory evaluation (hematologic and chemistry profiles), chest
radiography, and computed tomography (CT) of the abdomen and
pelvis.[2] Computed tomographic scans of the abdomen may identify a
primary site in 10% to 35% of patients; CT scans may also locate
additional sites of metastatic disease.[3,4] Tumors identified by CT
scans of the abdomen and pelvis include those arising from the
pancreas, kidney, hepatobiliary tract, and ovary.

Additional procedures (eg, radiologic imaging and/or endoscopic
examinations) are warranted to evaluate specific presenting signs or
symptoms. Positron emission tomography (PET), performed with
fluorine-18-deoxyglucose, is a noninvasive technique that has
identified primary sites in a few patients, although its role in the
evaluation of patients with cancer of unknown primary site is
incompletely defined.[5,6]

Certain additional diagnostic evaluations should be performed in
specific patient subsets. For example, mammography should be
performed in women with clinical features suggestive of metastatic
breast cancer. All men with adenocarcinoma of unknown primary site
should have their serum prostate-specific antigen (PSA) levels
measured, as well as PSA staining of the biopsy specimen. Serum
levels of human chorionic gonadotropin (HCG) and alpha-fetoprotein
(AFP) should be measured in young men with poorly differentiated carcinoma.

The diagnostic yield of other additional diagnostic procedures is
low[7,8] (Table 1) and can add
considerable expense to the initial evaluation. Extensive radiologic
or endoscopic investigations of asymptomatic areas are rarely useful
in identifying a primary site.

Measurement of various commonly used serum tumor markers (eg,
carcinoembryonic antigen [CEA], cancer antigen 15-3 [CA 15-3], cancer
antigen 125 [CA-125], and cancer antigen 19-9 [CA 19-9]) also is not
useful in providing clues to the location of the primary site. All of
these markers are frequently elevated in patients with carcinoma of
unknown primary site, and thus, provide no diagnostic or prognostic
information.[9] Modest elevations of HCG or AFP (ie, levels of either
marker < 100) are also of no diagnostic or prognostic utility in
this patient population.[10] If levels of any of these markers are
elevated, serial measurement may be useful in assessing response to treatment.

Pathologic Evaluation

An accurate pathologic evaluation of tumor tissue is an essential
part of the diagnostic process. A biopsy of the most accessible
lesion should be performed. A fine-needle biopsy is least invasive
but may not yield enough tissue for specialized pathologic studies,
which are required for all patients with poorly differentiated
tumors. Close collaboration with the pathologist is therefore
necessary to ensure that optimal diagnostic studies are performed.
The pathologist should be informed about all of the clinical
information to assist in the selection of specialized pathologic studies.

Light microscopic examination results in the identification of
several subgroups, including poorly differentiated neoplasms, well-differentiated
and moderately well-differentiated adenocarcinomas, squamous cell
carcinomas, and poorly differentiated carcinomas (with or without
features of adenocarcinomas). Histochemical staining for mucin may
facilitate identification of some adenocarcinomas.[11]

In patients with well-differentiated or moderately differentiated
adenocarcinoma, further pathologic studies rarely identify a primary
site and are only indicated in selected patient subgroups. Staining
for PSA occasionally identifies a prostate primary site in men with
metastatic adenocarcinoma, and positive staining for
estrogen/progesterone receptors is useful in women with clinical
features compatible with metastatic breast cancer.

As opposed to their limited utility in patients with adenocarcinoma,
additional pathologic studies frequently add useful information to
the evaluation of poorly differentiated tumors. Immunocytochemical
stains are now widely available and should be routinely performed.
Although definitive diagnoses can be made only in a minority of
patients, a number of diagnoses can be suggested with this technique,
including lymphoma, melanoma, sarcoma, and neuroendocrine carcinoma (Table
). Several of these diagnoses have specific therapeutic implications.

A number of “tumor-specific” antibodies or antibody panels
have been evaluated. However, none of these is sufficiently specific
to reliably identify a primary site.[12-15]

Electron microscopy is also a valuable tool in the evaluation of
poorly differentiated tumors. Since it is less widely available and
often requires rebiopsy with special tissue preparation, electron
microscopy should be reserved for use in tumors of uncertain lineage
following immunoperoxidase studies. Definitive diagnoses of lymphoma,
neuroendocrine tumors, melanoma, and a variety of sarcomas is
possible with electron microscopy.


When a primary site is definitively identified by either clinical or
pathologic evaluation, treatment should proceed according to the
guidelines for that type of cancer. In the large majority of
patients, however, no primary site can be identified. In these
patients, it is probably best to avoid the temptation to
“guess” at a primary site based on either suggestive
clinical or pathologic features.

For example, patients with mucin-positive adenocarcinoma involving
the liver may have an unidentified gastrointestinal primary, and yet
empiric treatment with gastrointestinal regimens (eg, fluorouracil [5-FU]/leucovorin)

has shown very little benefit in this group.[16] Therefore, empiric
treatment for carcinoma of unknown primary site should be employed
(see below), rather than relatively ineffective treatment for a
presumed insensitive primary site.

While, as mentioned above, it is not particularly helpful to label
patients with a presumed primary site, it is important to identify
patients who fall into certain treatable subsets, based on either
clinical or pathologic features (see below). Specific treatment
guidelines are available for these subsets. In the remainder of
patients, empiric treatment designed for cancer of unknown primary
should be employed.


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