Diagnosis

By definition, CUP is found after it has metastasized beyond its place of origin. Doctors use many tests in an effort to locate the primary site. Some tests may also determine which treatments may be the most effective. For most types of cancer, a biopsy is the only way to make a definitive diagnosis of cancer. Imaging tests will likely be used to look for additional areas where the cancer has spread.

Biopsy. A biopsy is the removal of a small amount of tissue for examination under a microscope. Other tests can suggest that cancer is present, but only a biopsy can make a definite diagnosis. The sample removed during the biopsy is analyzed by a pathologist (a doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease; see below). The type of biopsy performed will depend on the location of the cancer.

Evaluation by a pathologist

A pathologist makes the diagnosis of cancer by examining a sample of the tumor obtained through a biopsy. The results of the initial biopsy provide important information and guide further evaluation. Most cases of CUP fall into these four categories:

Adenocarcinoma. Nearly 60% of all cases of CUP are adenocarcinoma. Adenocarcinoma can arise in most internal organs (for example, lung, stomach, pancreas, colon, ovary, and breast). When found in a metastatic site, it is extremely difficult for the pathologist to tell the site of origin.

Poorly differentiated carcinoma. Nearly 20% to 30% of all CUP cases are poorly differentiated carcinomas. These cancers require extra tests by the pathologist, since some very treatable cancers may initially be diagnosed as poorly differentiated carcinoma. If testing identifies lymphoma, germ cell carcinoma, or neuroendocrine carcinoma, effective treatments are often available. When evaluation does not identify more specific tumor types, some patients with poorly differentiated carcinoma may still be treated successfully with chemotherapy.

Squamous cell carcinoma. Nearly 5% to 10% of all CUP cases are squamous cell carcinoma. Effective treatments are available for tumors with certain characteristics. If squamous cell carcinoma involves the cervical (neck) lymph nodes, the primary site is often in the head and neck area. If it involves the inguinal (groin) lymph nodes, the primary site may be in the vulva, vagina, cervix, anus, or bladder. A careful search is important, since most of these cancers can often be treated successfully.

Neuroendocrine carcinoma. Nearly 1% to 5% of all CUP cases are neuroendocrine carcinoma. These cancers are being recognized more frequently when specialized pathologic staining is performed. Some of these tumors are aggressive and fast growing, but are responsive to combination chemotherapy. Others are very slow growing, and patients sometimes live for several years even without treatment.

Clinical evaluation (evaluation by an oncologist)

Once a diagnosis of CUP is made, an oncologist (a doctor who specializes in treating people with cancer) will do further tests to search for the primary site and to determine how far the cancer has spread. However, most patients with CUP, the primary site is not found even after extensive evaluation. For this reason, several diagnostic tests (described below) may be done in order to evaluate specific signs and symptoms. The following tests may be recommended:

Medical history. The doctor will ask detailed questions about previous illnesses, surgeries, and medications. The doctors can help more if they also know as much information as possible about smoking history, drug use, previous moles or benign (noncancerous) tumors, and any exposure to radiation, asbestos, or other known dangerous chemicals. Family history of cancer may also provide important clues, especially if one or more siblings, parents, or grandparents have had breast, ovarian, or colorectal cancer.

Physical examination. The doctor will do a thorough physical examination of the entire body, including lymph nodes, pelvis, breasts, rectum, and genitals.

Blood and urine tests. These tests can tell if certain tumor markers and proteins are present that may help identify where the cancer began. Tumor markers are substances found at higher than normal levels in the blood, urine, or body tissues of some patients with cancer. Tumor markers are produced either by the tumor or by the body as a result of cancer or other conditions. For example, presence of the Epstein-Barr virus (EBV) may indicate nasopharyngeal cancer in patients who have cancer in the neck lymph nodes. Elevated levels of the proteins human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) may lead to the diagnosis of germ cell tumor in young men with poorly differentiated carcinoma.

X-ray. An x-ray is a picture of the inside of the body. For instance, a chest x-ray can help doctors determine if the cancer has spread to the lungs.

Computed tomography (CT or CAT) scan of the chest and abdomen. A CT scan helps doctors determine the location and extent of the cancer. A CT scan creates a three-dimensional picture of the inside of the body with an x-ray machine. A computer then combines these images into a detailed, cross-sectional view that shows any abnormalities or tumors. Sometimes, a contrast medium (a special dye) is injected into a patient’s vein to provide better detail. The CT scan can show cancer in other parts of the abdomen and chest.

Positron emission tomography (PET) scan. A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive substance is injected into a patient’s body and absorbed by the organs or tissues being studied. This substance gives off energy that is detected by a scanner, which produces the images. PET scans have proven useful in detecting a primary site in 20% to 30% of patients with CUP. For this reason, the PET scan is now considered a routine part of the initial evaluation. Even when a primary site is not identified, a PET scan can sometimes provide information that is useful in treatment planning. For example, in patients who have a single area of cancer involvement where local treatment (surgery or radiation therapy) is being considered, a PET scan can rule out other unsuspected areas of cancer involvement. When used in conjunction with CT scans, the information obtained is more detailed and specific than that obtained with either scan alone.

Magnetic resonance imaging (MRI). An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. A small amount of a radioactive substance is injected into a patient’s body and absorbed by the tissues or organs being studied. This substance gives off energy that is detected by a scanner, which produces the images. In some parts of the body, especially the brain and vertebral column, the MRI scan provides more information than the CT scan. In addition, women with cancer in the axillary lymph nodes (under the arm) should have a breast MRI scan, since this test can sometimes detect a small breast cancer that goes undetected by a mammogram (x-ray of the breast; see below).

Endoscopy. This test allows the doctor to see inside the body. The person may be sedated, and the doctor inserts a thin, lighted, flexible tube called an endoscope through the mouth and down the esophagus. The specific procedures are named according to the part of the body. For example, a bronchoscopy allows doctors to look inside the bronchial tubes (lungs), and a colonoscopy allows doctors to look inside the colon and rectum. Endoscopy is used in patients with CUP to evaluate the specific symptoms. For instance, patients with squamous cell carcinoma involving neck lymph nodes should always have a complete endoscopy of the nasopharynx, throat, and larynx (voice box) to search for a primary site.

Prostate-specific antigen (PSA) test. Prostate-specific antigen (a type of protein released by prostate tissue) is a substance found in a man's blood when there is abnormal activity in the prostate, including prostate cancer, benign prostatic hyperplasia (BPH), or prostatitis (inflammation of the prostate). Men who are experiencing bone pain will have a PSA test. A PSA test detects higher than normal levels of PSA, which may indicate the presence of prostate cancer.

Mammogram. Women may receive a mammogram (x-ray of the breast), especially if they have cancer in the axillary lymph nodes or other areas that might suggest metastatic breast cancer (for example, fluid around the lungs or bone involvement).

When the clinical and pathologic evaluation is finished, answers to the following questions are essential in helping doctors plan treatment:

• Did the clinical and imaging evaluation succeed in locating a primary site? If so, treatment should proceed according to guidelines for an advanced (metastatic) tumor of that primary site.
  
  
• Did the pathologic (biopsy) evaluation identify a specific tumor type (for example, lymphoma or germ cell tumor) or a primary site? If so, treatment should follow guidelines for the specific tumor type.
  
  
• If no primary site was identified, does this CUP fit into any of the subgroups for which specific treatment is recommended (see Treatment)?
  
  
• If no primary site was identified and this CUP does not fit any of the subsets with specific treatments defined, will chemotherapy (based on the doctor’s experience and evaluation of each patient individually) be beneficial? The chance of chemotherapy being successful depends on the location of the tumor, number of tumors involved, and the person's overall health at the time of diagnosis.

To learn more about what to expect during common diagnostic tests, read Cancer.Net: Tests and Procedures.

To learn about the terms used in this section, read the Cancer.Net Feature: Cancer Terms to Know: Newly Diagnosed.